In 1981, a new disease syndrome appeared in human populations in the United States and elsewhere characterized by a deficiency in the immune system . Patients presented with unusual infections and cancers such as Pneumocystis jiroveci (carinii) pneumonia and Kaposi's sarcoma. This acquired immune deficiency syndrome (AIDS) consisted of a marked reduction in CD4+ cell numbers and enhanced B-cell proliferation and hypergammaglobulinemia. This latter finding most likely reflects immune activation, which has recently been reappreciated as a major cause of the pathogenic pathway. In this regard, chronic inflammation has received better attention as a cause of cancer, cardiovascular diseases, and other comorbidities appearing in long-term HIV-infected people. Two years after the recognition of AIDS, the causative agent, a human retrovirus in the lentivirus family, was identified [2–4]. Early observations had indicated this virus was spread through intimate sexual contact (e.g., genital fluids), blood and blood products, and through mother-to-child transmission . Although those three means of transmission have not changed, great progress has been achieved in preventing mother-to-child transmission with antiviral drugs and HIV infection from contaminated transfused blood and blood products.
The discovery of HIV led rapidly to its cloning and the identification of its genes, as well as efforts to find treatment and prevention, particularly through a vaccine. Within the past 10 years, effective antiviral therapies have become available directed at the major enzymes of the virus (reverse transcriptase, protease, and integrase) as well as its attachment and fusion sites . These drugs offer great hope to those at risk of advancing to AIDS, and their availability in resource-limited countries remains an important priority. Long-term therapy, however, may not be possible because of toxic drug side effects and drug resistance . Other treatments are needed, and a cure of HIV infection, if at all possible, is a major challenge. Importantly, the successful development of an effective vaccine would have the most long-ranging effects on the epidemic.
This review will highlight the background and progress made over the past 25 years in understanding many aspects of HIV pathogenesis. This field has been extensively reviewed in a recent monograph , so only brief summaries of some topics will be given. Particular attention is placed on findings reported most recently that continue to contribute to our knowledge of HIV and its pathogenic course. Several challenges still facing the field are discussed.
Since the discovery of HIV, epidemiological and genetic studies have indicated that the AIDS viruses, HIV-1 and HIV-2, consist of different virus groupings. Variations primarily in the envelope genes help distinguish them. The virus groups differ by at least 30% whereas the clades (subtypes) differ by 15–20%. Only HIV-1 has subtypes or clades of which nine have been recognized (A–D; F–H; J–K). The original clades E and I have been identified as recombinant viruses [8–10], and clade G may also fit best into this category . Of the three main groups of HIV-1, M, N, and O, the majority of infections occur with group M; about 100 000 infections have occurred with group O. Very few infections have taken place with group N. HIV-2, discovered about 2 years after HIV-1 , differs by 40% and consists of eight different groups of which A and B are the most prominent. These HIV-1 and HIV-2 groups and HIV-1 subtypes are now distributed throughout the world; all are found in Africa .
HIV-1 clade C is becoming the most prevalent transmitted virus. Its wide transmissibility could reflect the high viremia set point in clade C infections and the higher virus levels found in genital fluids than found with other clades . Moreover clade C viruses have three NFκB sites in comparison to one to two in other clades . During immune activation, the NFκB sites make HIV more responsive to cytokines such as TNF-α that enhance virus production.
An important finding in the last decade has been the emergence of recombinant viruses forming in several regions of the virus between HIV clades and groups (Fig. 1). Recombination between HIV-1 and HIV-2 has not been reported and probably cannot form because of differences in the location of the RNA dimer hairpin sites . Virus recombinations can occur particularly after coinfection or superinfection of cells by two or more viruses prior to the establishment of a chronic infection. In the latter case, the downmodulation of the CD4 molecule would create a resistant state. Superinfection is common in viral infections , and, thus, its occurrence in HIV is not surprising and has been reported even in long-term healthy individuals . Obviously, control of multiple HIV infections within an individual is possible. Nevertheless, this process can lead to recombinant viruses resistant to certain drugs and immune responses . Thus far, superinfection is being detected more often during the early stages of HIV infection than in chronic infection .
HIV-1 and HIV-2 are retroviruses with both structural and accessory genes. The latter determine the extent of their replicative and pathogenic characteristics that vary among HIV-1 groups and clades. For example, group M clades appear to replicate 100-fold better than group O or HIV-2 isolates . In addition, clade A virus infections have a slower disease course than infections with other clades . HIV-2 has a lower transmission rate and a less pathogenic course resembling, in part, the asymptomatic infection of the simian immunodeficiency virus (SIV) in sooty mangabeys and African Green Monkeys (AGMs) . These observations most likely reflect less immune activation (see below). Moreover, HIV-2 has lower progeny virus production and thus less infectious virus in body fluids .
Comparison of the biologic and genetic properties of viruses from the same individual has suggested independent evolution in distinct compartments; for example, blood, lymphoid tissue, oral cavity, central nervous system, genital fluids, and gastrointestinal tract [25–27]. This viral heterogeneity is now more easily defined through novel innovative technologies for genome sequencing, such as detecting single nucleotide polymorphisms (SNPs) through pyrosequencing  and other procedures.
The initially observed HIV macrophage-tropism and T-cell line-tropism are determined primarily by the coreceptor used along with CD4 for virus attachment to cells. Macrophage-tropic viruses utilize the chemokine receptor, CCR5, and are known as R5 viruses. Viruses infecting established T-cell lines use the CXCR4 receptor and are known as X4 viruses . These latter viruses are generally more cytopathic than R5 viruses and were initially called syncytium-inducing in contrast to the non-syncytium-inducing R5 viruses . Individuals who lack CCR5 expression are resistant to R5 virus infection but are susceptible to X4 viruses (see below). A large number of other chemokine coreceptors can also act as primary or secondary attachment sites for both HIV-1 and HIV-2 isolates (e.g., CCR3, CCR2b) but are not commonly involved in infection [24,29,31]. In addition, besides CD4, galactosyl ceramide (GalC) can serve as a major binding site for HIV-1 infection in the bowel, vagina, and brain [32–34]. Moreover, HIV complexed with antibodies can gain entry into T cells and macrophages and other cells through Fc and complement receptors [35,36].
Over the past 10 years, a variety of additional cellular binding proteins have been found associated with HIV infection. Among these, the most common are the C type lectins, particularly DC-SIGN, as well as the leukocyte function-associated antigens (LFAs) and the intercellular adhesion molecules (ICAMs) [37,38]. Most recently, the α4β7 integrin has been identified as an HIV-binding site particularly on CD4+ memory T cells  – a possible explanation for the loss of these cells in the gastrointestinal tract during early infection. (See below).
Transmission of HIV is dependent on the biologic properties of the virus, its concentration in the exposed body fluid, and the nature of the host susceptibility both at the cellular and immunological levels. In this regard, a recent study has suggested that the initial infection by HIV occurs in most patients by a single virus . If confirmed, this low level of virus transmission offers a ‘window of opportunity’ to prevent transmission using a drug or vaccine. Importantly, with transmission of most viral infections, a free virus is involved. In the case of HIV, integration of the virus into the cellular chromosome establishes virus-infected cells as sources of transmission . They can transfer HIV to cells of both the immune system (e.g., T cells, macrophages, dendritic cells) as well as mucosal cells lining the vaginal and anal canals [42,43] (Fig. 2). The transmission of HIV is associated with large amounts of virus in the genital fluids, which are often found (but not always) with high plasma viral loads . These findings are most common with advanced disease and during acute infection when the risk of transmission can be increased over 20-fold .
Sexually transmitted diseases increase both infectious virus and infected cells in genital fluids and can enhance HIV transmission . The lack of circumcision has been linked to an increased risk of infection for males , and transmission has been reduced by circumcision of male adults . This observation can be explained by the large number of HIV-susceptible dendritic cells in the foreskin . Moreover, inflammation often found with the prepuce provides more target cells for infection by HIV encountered through the vaginal, anal, and oral routes.
Studies using SIV suggest that the cervix is the first tissue infected after intravaginal virus inoculation . Within 2 days, the cervix is infected and the virus then spreads most likely through dendritic cell (and CD4+ cell) migration to regional lymph nodes and subsequently into the blood stream. Passage of virus-infected cells in semen through the cervical os into the uterus would appear to be a major route of transmission to women. For this reason, diaphragms were evaluated as a preventative measure but were used in the trials most often in addition to male condoms . Thus, their independent value could not be evaluated. Some infected people have been identified as super-producers of virus in seminal fluids . In certain cases, the presence of specific amyloid fibrils in semen may enhance the rate of HIV transmission by increasing virus attachment to cells .
Early virus–host cell interactions
HIV infection results first from virus attachment to a major receptor and then generally further binding through coreceptors and other adhesion molecules. Subsequently, virus–cell fusion takes place, most likely between the virus gp41 and a fusion receptor on the cell, perhaps a glycolipid. This interaction permits the HIV capsid to enter the cell. Reverse transcription and integration then take place primarily in cells that are activated . These HIV-infected cells become persistent reservoirs for the virus and sources of transmission. During early infection, the induction of chemokines can bring more target cells to the site of infection and inflammation . Thus, these cellular products can increase virus spread rather than prevent it by their antiviral activity .
Observations over the past 25 years have indicated that many cells in the body (e.g., brain, bowel, kidney, prostate) can be infected by HIV besides cells of the immune system . Thus, attempts to cure HIV infection must consider all of its cellular reservoirs. Importantly, HIV has been shown to integrate into resting CD4+ T cells, even at a low virus input . This finding could explain the detection of integrated HIV in immunologically naive CD4+ T cells .
Virus infection can be blocked at entry, prior to reverse transcription, after reverse transcription, or after integration into an infected cell. In the latter case, latency or a silent infection can result. (See below). Virus integration and established infection does not take place unless the cell is activated within a few days after virus entry .
Presence of virus subtypes during HIV infection
Several studies have indicated that R5 viruses are generally first observed in the blood during acute or early infection . Later, in association with disease, the more cytopathic X4 virus emerges. In about 50% of AIDS cases, an R5 virus is found though it shows biologic properties associated with virulence in the host . It replicates more rapidly, produces high amounts of progeny virus, and induces cytopathology. Some studies suggest that the initial infecting R5 virus often evolves into a dual-tropic R5/X4 virus and then to an X4 virus . Specific genetic alterations in the envelope regions of the infecting R5 virus have been shown to be responsible for the change in coreceptor usage . Alternatively, the early R5 virus infection may be followed by an X4 virus infection resulting from the reemergence of a related X4 virus that coinfected the individual at the time of initial transmission. The processes influencing these events, which include a compromise to the immune response, have not yet been fully defined .
The reasons suggested for R5 virus predominance during acute and primary infection include the following:
- R5 viruses have many susceptible CCR5+ CD4+ T-cell targets during immune activation;
- R5 viruses can more readily infect nonactivated cells;
- R5 viruses can infect macrophages and dendritic cells;
- higher R5 progeny virus production takes place in infected cells;
- R5 viruses preferentially infect CCR5-expressing CD4+ cells in the gastrointestinal tract;
- R5 viruses are less recognized by the immune system [e.g., cytotoxic T-lymphocytes (CTL)].
Chronic and late HIV infection
About 6 months after the acute infection phase, most infected individuals enter into an asymptomatic period in which virus levels in the blood reach a set point often below 20 000 RNA copies/ml. This event reflects primarily the antiviral responses of the innate and adaptive immune systems. (See below). Circulating innate factors such as mannose-binding lectins (MBLs) and complement could be involved. Anti-HIV antibodies, as well as natural killer (NK) and T cells, play important roles. In some infected individuals, an absence of detectable viremia indicates efficient HIV control; this unusual group has been termed ‘elite controllers’ . HIV replication during the subsequent persistent infection period can take place at low levels in the lymph nodes and other tissues and appears to reflect the extent of control by antiviral immune responses.
After 10 years of infection, about 50% of the individuals without therapy will begin to develop signs of the infection including a decrease in CD4+ T-cell counts below 350 cells/μl  and loss of immune activities (specifically HIV-specific CD4+ and CD8+ T-cell responses). Viral destruction of lymphoid tissue mirrors this progression of HIV infection . As noted above, the virus at this time can have an X4 phenotype or be a R5 virus with virulence properties. In industrialized countries, infected individuals are treated with anti-HIV drugs once the persistent period goes into this symptomatic phase.
In some cases, HIV infection can result in a silent infection showing no evidence of virus progeny production. This HIV latency can involve the site of virus integration, its state after integration (e.g., methylation), and the absence of sufficient viral Tat or Rev expression . In addition, a variety of cellular proteins such as histone deacetylase (HDAC), YY1, and the CD8+ antiviral factor can lead to a suppression of virus infection in the infected cell [66–68]. Importantly, cellular intrinsic antiviral factors can be involved (Section ‘Intrinsic intracellular factors’). Attempts to activate HIV from latent reservoirs with a variety of compounds have not shown beneficial clinical results, though these compounds may induce HIV replication in vitro .
What factors influence the HIV pathogenic course
CD4+ cell loss
Destruction of CD4+ T cells is a primary reason for the opportunistic infections and cancers associated with HIV infection. Many factors can be involved in this CD4+ cell loss (Table 1).
For example certain cytokines (e.g., TNF-α) and HIV proteins (e.g., Tat, Nef, Vpr, Vpu) can influence the extent of HIV replication and CD4+ cell death. Other processes involved in this CD4+ cell loss can include the conventional disruption in metabolic processes and cell membrane integrity by HIV causing necrosis. In many cases, apoptosis results from direct virus infection or an indirect effect of immune activation (see below). More recently, autophagy has been noted as a possible cause of bystander CD4+ cell death with HIV infection . Another reason can be CD8+ cytotoxic T-cell (CTL) activity against normal CD4+ cells . The reduction in the peripheral blood CD4+ cell count over time also results from a block in T-cell restoration processes in the thymus .
A major effect of acute HIV infection is the widespread destruction of memory CD4+ cells in the gastrointestinal tract . These T cells in the mucosal-associated lymphoid tissue (MALT) can induce the overall immune responses of the host. In addition, an interruption in the integrity of the gastrointestinal epithelium permitting bacteria to enter the blood can cause inflammation and activation that encourage further CD4+ cell loss . To what extent this latter process contributes to pathogenesis is actively under study.
Probably the most important concept that has reemerged as an important component of HIV pathogenesis is chronic immune activation [75–78]. Hyperimmune responses with production of pro-inflammatory cytokines such as TNF-α can lead to enhanced HIV production and loss of CD4+ and CD8+ T cells through apoptosis  and other processes including perhaps immune senescence . The absence of this chronic activation in long-term survivors (though probably reflecting the low viremia) and importantly in natural nonpathogenic SIV infection models with high viral loads (e.g., sooty mangabey) support this conclusion [81,82].
In this regard, the pro-inflammatory cytokine, IL-17, associated with the CD4+ T-cell subset, TH-17, may be important in HIV infection. These cells help combat bacterial and fungal infections and have been found reduced in the gastrointestinal tract of HIV-infected patients but not nonpathogenic SIV infections . Whether these cells are also participants in immune activation merits further study.
Most recently, the production of IFN-α by plasmacytoid dendritic cells (PDCs) has been cited as contributing to immune activation . PDCs isolated from sooty mangabeys with chronic SIV infection show low IFN-α production in vitro, in association with reduced immune activation . Other factors that may explain this observation in natural SIV-infected hosts include activation of Tregs, upregulation of PD-1 expression, lack of microbial translocation, and downmodulation of the TCR-CD3 complex by Nef . Obviously, factors inducing vs. reducing immune responses and the time of this expression must influence the clinical course (see Conclusions).
Cofactors in HIV pathogenesis
Microbial infections can enhance (e.g., herpesvirus) or delay (e.g., GB virus C) HIV pathogenesis . Importantly, certain polymorphisms in the human histocompatibility locus can affect the strength of the cellular immune anti-HIV responses  (Table 2).
Other genetic differences shown to influence disease progression include the relative expression of the chemokine receptors (e.g., CCR5), chemokines, and other cytokines (Table 3) (refer http://www.hiv-pharmacogenomics.org). Moreover, homozygosity for variant MBL2 alleles has been associated with an increased risk of HIV infection and progression to AIDS [88,89]. A reduction in the level of this innate antiviral protein or its altered structure or both seems involved . Most recently, apolipoprotein E4 has been implicated in accelerating HIV-related disease .
Intrinsic intracellular factors
The importance of natural intracellular anti-HIV resistance factors has recently been highlighted. APOBEC3G (and 3F), a cytosine deaminase, alters single-stranded DNA synthesis during reverse transcription ; it causes the production of an inactive DNA product that is degraded by the cell. The viral protein Vif interacts directly with APOBEC3G (and 3F) and prevents its activity by blocking the incorporation of APOBEC into viral particles [91,92]. Other processes may also be involved. Recent studies have suggested that a higher expression of APOBEC3G and 3F within the cell is associated with lower viral replication during acute infection . Moreover, these cellular proteins could be responsible for the resistance or latent infection of resting CD4+ cells .
Another intracellular factor, TRIM5α, regulates the ability of certain retroviruses to infect human cells and for HIV to infect monkey cells. This gene appears to interact with the viral capsid and prevent uncoating . Other activities such as reverse transcription may also be blocked.
This last year, HIV Vpu has been shown to prevent the activities of a human cellular membrane protein, tetherin , and a calcium-modulating cyclophilin ligand  that block budding of the virus particle from the cell surface. Moreover, host genome-wide screening has suggested many other intracellular proteins needed for HIV replication that could be targets for anti-HIV therapy [98–100].
Host anti-HIV immune responses
The host immune response consisting of humoral and cellular components of innate and adaptive immunity greatly determines the clinical course. The key difference between these two major immune systems is the quick response of the innate system to an incoming pathogen; a microorganism can be recognized in minutes to hours against days to weeks observed with the adaptive immune system. Innate immunity responds to a conformational pattern of a pathogen rather than a specific epitope .
Innate immune responses
MBLs and complement, that can readily inactivate virus, are important soluble anti-HIV innate immune factors [88,89,102,103]. Moreover, other circulating proteins can block HIV infection [104,105]. Naturally occurring anti-Tat IgM antibodies can inhibit the effects of Tat , and naturally occurring IgM antileukocyte autoantibodies  could prevent HIV entry into cells.
Neutralizing antibodies against the HIV envelope gp120 and gp41 can have great importance as adaptive immune responses. In some situations, antibodies to cell surface proteins [e.g., LFA, ICAM, human leukocyte antigen (HLA)] can mediate this activity [108,109]. Genetic and nongenetic factors have been shown to influence this sensitivity to neutralization including linear and conformational epitopes as well as the degree of envelope glycosylation and stability. Some antibodies may interact with a cluster of oligomannose glycans on gp120, suggesting another direction for vaccine development .
Several monoclonal antibodies have been derived from human sera that react with gp120 or gp41 and have broad anti-HIV reactivity. This observation indicates that this objective can be achieved. These antibodies recognize a consensus sequence (or carbohydrate moiety) shared by a variety of different HIV-1 and HIV-2 groups or clades . More recently, a neutralization epitope has been revealed on gp120 after an interaction with CD4. This approach could be used to develop immunogens that will direct antibodies to that region in gp120, now called CD4-induced or CD4i antibodies [112,113].
Antibodies that attach to virus-infected cells (via gp120 or gp41) can also be important in direct killing of infected cells by antibody-directed cellular cytotoxicity (ADCC). This process, mediated through the Fc receptor primarily by NK cells, is found in healthy infected individuals and correlates with a clinically healthy course .
Enhancing antibodies and autoantibodies
At the same time that neutralization of HIV is an important parameter of protection, antibodies that attach with less affinity to the virus need to be appreciated. They can facilitate HIV infection of T cells, macrophages, and other cells through the Fc or the complement receptor [35,36]. This antibody-mediated enhancement of HIV infection can be associated with development of disease . Circulating autoantibodies to hematopoietic cells, such as red cells, neutrophils, and CD4+ cells, may also contribute to HIV pathogenesis .
Dendritic cells play a role in both innate and adaptive immune activities in HIV infection. They are antigen-presenting cells (APCs) for T and B cells and produce cytokines that influence the immune response . Various dendritic cell types are found throughout the body . Blood dendritic cells consist of PDCs and myeloid dendritic cells (MDCs). The MDC is the major APC in the blood.
The PDC, a CD4+ lineage negative cell, is a precursor dendritic cell that can direct type 1 or type 2 immune response in a type 1 and type 2 manner . It is found in lymphoid tissue in the CD4+ cell region and at low numbers in the blood (2–8 cells/μl). This cell is the major producer of type-1 interferons (IFNs) after exposure to viruses and other pathogens . It expresses the chemokine coreceptors and can be infected by HIV but at low sensitivity . Reduced PDC number is associated with the development of AIDS . Notably, long-term survivors (see below) have higher levels of this cell type than even healthy controls . Moreover, in acute HIV infection, the PDC number is inversely related to the viral load . Those acutely infected individuals with a low viral load and high PDC could become long-term survivors.
These findings support the conclusion that PDC and IFN are beneficial in HIV infection. Nevertheless, other studies indicate that early viremia can lead to an increase in PDC and IFN production that can cause enhanced and chronic immune activation [84,124]. Thus, the relative beneficial vs. detrimental roles of PDC and IFN need to be considered (see Conclusions).
Other innate immune cells
NK cells have an important function in destroying HIV-infected cells and are influenced by the production of cytokines such as IFNs and IL-12. They kill infected cells that lack major histocompatability class (MHC) I expression. The interaction of NK-inhibiting receptors (KIRs) on NK cells with certain HLA moieties can prevent this activity. The enhanced expression of KIRs, in the presence of HIV viremia, can suppress NK cell function . Nevertheless, a beneficial clinical course has been associated with NK KIR 3DL1 and its BW4-801 ligand . Other innate cells receiving attention in HIV infection are NKT  and γδT cells , but their clinical relevance in HIV pathogenesis has not been well-defined.
CD4+ T lymphocytes
CD4+ T cells, through cytokine production, have a major role in helping the immune response of B cells and other T cells. Some CD4+ cells can have a cytotoxic activity . CD4+ T-cell help is particularly important for the efficient function of CD8+ T-cell immunity. Although CD4+ cells have conveniently been divided into TH1 and TH2 subsets, depending on the cytokines they produce, the polyfunctionality of CD4+ T cells (and CD8+ T cells) is more clinically relevant . T-cell coproduction of IL-2 and IFN-γ appears to be beneficial for anti-HIV immunity [87,130]. The interaction of CD4+ cells with dendritic cells plays an important role in determining their production of specific cytokines. Strong HIV-specific CD4+ cell responses alone and particularly in association with HIV-specific CD8+ cells provide a good prognosis for the clinical course [131,132].
CD8+ T lymphocytes
Noncytotoxic activity: Simillar to dendritic cells, CD8+ cells can function in both the innate and adaptive immune systems. A CD8+ cell noncytotoxic antiviral response (CNAR), mediated by a novel as yet unidentified CD8+ cell antiviral factor (CAF), blocks virus transcription without killing the infected cell . CNAR/CAF appears to be an innate immune activity  that differs therefore from the conventional adaptive cytotoxic CD8+ CTL antiviral response that kills HIV-infected cells expressing specific viral epitopes. CNAR is found highest in long-term survivors (LTS); when this activity decreases, virus replication resumes with progression to disease . This new type of cellular noncytotoxic antiviral response has since been observed in SIV and FIV infections as well as several other viral infections, including hepatitis B, C, cytomegalovirus, and herpes simplex virus [67,133–135].
Cytotoxic activity: The classic CD8+ cell participates in an adaptive immune activity by which the virus-infected cell is killed. This CTL response has been associated with long-term control of HIV infection, and anti-Gag responses appear to correlate best with the anti-HIV activity [136,137]. Nevertheless, the presence of CTLs in patients with AIDS has raised questions about this T-cell's role in influencing the disease course. CTL activities can be detrimental if they lyse autologous uninfected CD4+ cells and APCs . Importantly, CTLs may remain HIV-specific but not have the capacity for killing virus-infected cells because of the absence of perforin or other cytotoxic proteins . In some cases, immune senescence may be involved . Moreover, some reports suggest that expression of the programmed death 1 protein (PD-1) on HIV-specific CD8+ T cells can reduce CTL function . If this member of the CD28 family of costimulation molecules interacts with one of two B7-related ligands (PD-L1 or PD-L2) on cells, CTL activity is blocked. Interruption in this interaction of PD-1 with its ligands can restore cell function [139,140].
Virus resistance to immune responses
HIV has a variety of mechanisms by which it can resist anti-HIV activities. These include mutations of the viral peptide, defective presentation by HIV-infected cells, and incorrect expression of viral peptides by APCs. Viral escape mutants are more commonly encountered in acute infection in which the more dominant epitopes of viral proteins are first targeted . In chronic infections, escape mutants are less frequently responsible for resistance; the immunodominant regions are usually conserved epitopes that can be better controlled . No virus resistant to CNAR/CAF has been found . Resistance to neutralizing antibodies involves mutations in the targeted envelope epitope.
T regulatory cells
CD4+ T regulatory (Treg) cells have received increased attention in HIV infection. These cells can be identified by several phenotypic markers, different functions, and various mechanisms of action [143–145] (Table 4).
Importantly, they may be beneficial early in HIV infection by decreasing immune activation but detrimental later if they decrease the antiviral immune response. A bimodal response with Treg cell activity, early but not late, can be observed in the SIV nonpathogenic primate models [144,145]. The potential presence of CD8+ Treg cells in HIV infection should also be considered .
As observed in all viral infections, some HIV-infected individuals can survive and show no signs of disease for many years. Such LTSs, also called long-term nonprogressors, represent about 5% of infected individuals. They have been infected for more than 10 years (some over 30 years) and remain healthy with normal CD4+ cell counts without receiving antiretroviral therapy. LTSs have a variety of features such as mutations in the infecting virus itself (lack the Nef protein), host immune responses (certain genetic polymorphisms, particularly in HLA), and notably important cellular (NK, CD8+ cell) anti-HIV immune responses.
Factors influencing long-term survival include the following:
- Infection with a low replicating virus or an attenuated HIV strain (nef-mutated) with a reduced replicative ability;
- Strong cell-mediated anti-HIV immune response, particularly CD8+ cell cytotoxic and Noncytotoxic antiviral activity: depends on type 1 cytokine production;
- Genetic background (e.g., receptor polymorphisms – HLA B57; B27 and immune response, Table 3);
- Neutralizing antibody, lack of enhancing antibodies;
- Lack of one CCR5 allele.
With this control of viremia, comes a lack of immune activation. As noted above, a separate group of LTSs, now called ‘elite controllers’  do not have detectable plasma viral loads (<50 RNA molecules/ml). These individuals may reflect a different process from LTSs or greater levels of the immune activities maintaining long-term survival (Table 5).
High-risk HIV-exposed seronegative individuals
Another group of notable individuals have been exposed to HIV on many occasions and remain uninfected (Table 5). This exposure has been through sexual activity, intravenous drug use, transfusions, blood products, as well as children born of infected mothers and healthcare workers with needle sticks . This resistance, in some cases, appears related to genetic factors. An absence of CCR5 expression protects individuals from R5 virus infection, . Moreover, HIV-1-specific CD4+ cells  and CD8+ CTL anti-HIV responses, associated with certain HLA proteins, have been observed in exposed seronegative (ESN) individuals . And, the anti-HIV activity of NK cells, particularly those with specific KIR molecules (linked to HLA proteins), has been described in ESN [151,152]. Furthermore, the presence in ESN women of anti-HIV neutralizing antibodies in their cervical fluid but not their blood has been reported [153,154]. This latter finding, however, could not explain the protection from transmission by other routes. Innate immune activities associated with ESN such as the CD8+ cell noncytotoxic antiviral activity has been observed. This response is lost if exposure has not occurred within the last year . Recently, 15 proteins were found differentially expressed in cervical mucosae of ESN sex workers in Kenya , including several antiproteases such as the secretory leukocyte protease inhibitor that shows anti-HIV activity in saliva .
After 25 years of HIV research, we are poised at the point when we should focus on other targets for antiviral therapy, particularly the immune system, and ultimately find a cure for HIV infection. Moreover, with the recent failure of human vaccine trials, novel approaches for an effective vaccine need to be developed.
For new treatments, advances in whole genome screening [98–100] are showing promise for identifying new targets. Toward the cure for HIV infection, much further attention must be given to approaches to eliminate all infected cells, not just those in the immune system . They remain as persistent sources of virus for renewed spread and disease. This objective may be best achieved with immune-based therapies that ideally are initiated early in infection when the number of infected cells is limited. A real caveat is whether the truly latent cell can be identified and eliminated. Perhaps, approaches similar to that recently used to remove the HIV provirus without causing cell death  can offer a promising direction for a cure. At least, bringing infected individuals to the state of protection from disease as observed in long-term survivors would be a notable achievement.
An effective vaccine must induce broad neutralizing antibodies without enhancing antibodies and both innate and adaptive cellular immune anti-HIV responses. In this regard, the immunologic responses providing protection in exposed high-risk seronegative (ESN) individuals can give insight into the correlates of anti-HIV immunity (Table 5). Toward developing a vaccine, the induction of effective antiviral innate immunity, particularly in the mucosae, should be achieved. An appropriate adjuvant can elicit these beneficial immune responses that lead to effective adaptive immune memory responses. Notably, the rapid reaction of innate immunity could ‘wall off’ HIV at the first site of infection and prevent viral spread. Eventually, the infected cells would die off and the infection would be aborted. Such may be the case with ESNs. If not, at least the early response of innate immunity would permit time for the adaptive immune response to develop and prevent disease progression. What we have learned from other vaccines is that protection from disease is an easier achievement than protection from infection . Moreover, if vaccines can reduce HIV levels in body fluids, transmission would be reduced and the epidemic curtailed . A vaccine certainly seems feasible, particularly as retrovirus vaccines against the feline immunodeficiency virus (FIV) and the feline leukemia virus (FeLV) have been developed and involve protection from both free virus and virus-infected cells [161,162].
Among other challenges, certainly the emergence of recombinant viruses must be appreciated because of their ability to develop into new agents that can resist immune responses and antiviral therapies . For prevention, effective microbicides  are needed while we await a vaccine. Some have suggested giving antiviral therapy to uninfected people at risk of HIV transmission . This prevention approach needs consideration of the long-term effects of preexposure treatment. The events (e.g., chronic inflammation) leading to cardiovascular disease and other co-mobidities as well as cancers observed in HIV infection also merit further study. Some malignancies could result from immune enhancement as well as immune deficiency .
In achieving these objectives, several research questions would provide valuable insights (Table 6).
Among these unanswered questions is the appreciation that approaches at therapy or a vaccine must also recognize the beneficial and detrimental effects of immune activation (Section ‘Immune activation’). The nonpathogenic SIV models of natural infection offer some insights into this challenge. Immune activation following acute infection would be beneficial by inducing the innate and adaptive immune responses against the virus. Later, however, if a chronic immune-stimulated state remains, detrimental effects on the immune system, including apoptosis, can result. In this regard, control of immune activation may be brought about by the cellular production of indoleamine 2-3 dioxygenase (IDO). By depleting trytophan levels and other activities, IDO suppresses the activated immune system including IFN production [84,124,166]. Other counters to immune activation can be Treg cells and PD-1 expression [81,82,144,145]. However, these activities in extreme can also give negative effects as some continued activation of the immune system is required for effective long-term anti-HIV responses, both for treatment and a vaccine. Thus, the optimal condition is an early-stimulated anti-HIV immune response that is not an overreaction followed by the expression of factors that limit this response (Fig. 3) [82,84,124,144,146,166]. Toward this objective, we can learn a great deal from LTS and ESNs as well as the natural nonpathogenic SIV models. They provide valuable knowledge of immune system responses that are associated with a beneficial clinical course.
The author would like to acknowledge grant support (U01AI041531 and R01AI056992) from the United States National Institutes of Health and grants from the Campbell Foundation, the Stanley S. Langendorf Foundation, and the University-wide AIDS Research Program. The author thanks Brigitte Autran, Cecilia Cheng-Mayer, Alan Landay, and Guido Silvestri for their helpful comments, and Kaylynn Peter for assistance with the manuscript.
1. Gottlieb MD, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, et al
. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men. N Engl J Med 1981; 305:1425–1431.
2. Barre-Sinoussi F, Chermann J-C, Rey F, Nugeyre MT, Chamaret S, Gruest J, et al
. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983; 220:868–871.
3. Gallo RC, Salahuddin SZ, Popovic M, Shearer GM, Kaplan M, Haynes BF, et al
. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 1984; 224:500–503.
4. Levy JA, Hoffman AD, Kramer SM, Landis JA, Shimabukuro JM, Oshiro LS. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science 1984; 225:840–842.
5. Jaffe HW, Bregman DJ, Selik RM. Acquired immune deficiency syndrome in the United States: the first 1,000 cases. J Infect Dis 1983; 148:339–345.
7. Levy JA. HIV and the pathogenesis of AIDS. 3rd ed. Washington, DC: American Society of Microbiology; 2007.
8. Gao F, Robertson DL, Carruthers CD, Li YY, Bailes E, Kostrikis LG, et al
. An isolate of human immunodeficiency virus type 1 originally classified as subtype I represents a complex mosaic comprising three different group M subtypes (A, G, and I). J Virol 1998; 72:10234–10241.
9. Robertson DL, Sharp PM, McCutchan FE, Hahn BH. Recombination in HIV-1. Nature 1995; 374:124–126.
10. Anderson JP, Rodrigo AG, Learn GH, Madan A, Delahunty C, Coon M, et al
. Testing the hypothesis of a recombinant origin of human immunodeficiency virus type 1 subtype E. J Virol 2000; 74:10752–10765.
11. Abecasis AB, Lemey P, Vidal N, de Oliveira T, Peeters M, Camacho R, et al
. Recombination confounds the early evolutionary history of human immunodeficiency virus type 1: subtype G is a circulating recombinant form. J Virol 2007; 81:8543–8551.
12. Clavel F, Guetard D, Brun-Vezinet F, Chamaret S, Rey M-A, Santos-Ferreira MO, et al
. Isolation of a new human retrovirus from West African patients with AIDS. Science 1986; 233:343–346.
13. Peeters M, Toure-Kane C, Nkengasong JN. Genetic diversity of HIV in Africa: impact on diagnosis, treatment, vaccine development and trials. AIDS 2003; 17:2547–2560.
14. John-Stewart GC, Nduati RW, Rousseau CM, Mbori-Ngacha DA, Richardson BA, Rainwater S, et al
. Subtype C is associated with increased vaginal shedding of HIV-1. J Infect Dis 2005; 192:492–496.
15. Jeeninga RE, Hoogenkamp M, Armand-Ugon M, de Baar M, Verhoef K, Berkhout B. Functional differences between the long terminal repeat transcriptional promoters of human immunodeficiency virus type 1 subtypes A through G. J Virol 2000; 74:3740–3751.
16. Dirac AMG, Huthoff H, Kjems J, Berkhout B. Requirements for RNA heterodimerization of the human immunodeficiency virus type 1 (HIV-1) and HIV-2 genomes. J Gen Virol 2002; 83:2533–2542.
17. Levy JA. Is HIV superinfection worrisome? Lancet 2003; 361:98–99.
18. Casado C, Pernas M, Alvaro T, Sandonis V, Garcia S, Rodriguez C, et al
. Coinfection and superinfection in patients with long-term, nonprogressive HIV-1 disease. J Infect Dis 2007; 196:895–899.
19. Fultz PN. HIV-1 superinfections: omens for vaccine efficacy? AIDS 2004; 18:115–119.
20. Smith DM, Richman DD, Little SJ. HIV superinfection. J Infect Dis 2005; 192:438–444.
21. Arien KK, Abraha A, Quinones-Mateu ME, Kestens L, Vanham G, Arts EJ. The replicative fitness of primary human immunodeficiency virus type 1 (HIV-1) group M, HIV-1 group O, and HIV-2 isolates. J Virol 2005; 79:8979–8990.
22. Kaleebu P, French N, Mahe C, Yirrell D, Watera C, Lyagoba F, et al
. Effect of human immunodeficiency virus (HIV) type 1 envelope subtypes A and D on disease progression in a large cohort of HIV-1-positive persons in Uganda. J Infect Dis 2002; 185:1244–1250.
23. Rowland-Jones SL, Whittle HC. Out of Africa: what can we learn from HIV-2 about protective immunity to HIV-1? Nat Immunol 2007; 8:329–331.
24. Reeves JD, Doms RW. Human immunodeficiency virus type 2. J Gen Virol 2002; 83:1253–1265.
25. Keys B, Karis J, Fadeel B, Valentin A, Norkrans G, Hagberg L, et al
. V3 sequences of paired HIV-1 isolates from blood and cerebrospinal fluid cluster according to host and show variation related to the clinical stage of disease. Virology 1993; 196:475–483.
26. Wong JK, Ignacio CC, Torriani F, Havlir D, Fitch NJS, Richman DD. In vivo
compartmentalization of human immunodeficiency virus: evidence from the examination of pol
sequences from autopsy tissues. J Virol 1997; 71:2059–2071.
27. Fulcher JA, Hwangbo Y, Zioni R, Nickle D, Lin X, Heath L, et al
. Compartmentalization of human immunodeficiency virus type 1 between blood monocytes and CD4+ T cells during infection. J Virol 2004; 78:7883–7893.
28. Bushman FD, Hoffmann C, Ronen K, Malani N, Minkah N, Rose HM, et al
. Massively parallel pyrosequencing in HIV research. AIDS 2008; 22:1411–1415.
29. Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 1999; 17:657–700.
30. Tersmette M, de Goede REY, Bert JM, Al IN, Winkel RA, Gruters HTC, et al
. Differential syncytium-inducing capacity of human immunodeficiency virus isolates: frequent detection of syncytium-inducing isolates in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. J Virol 1988; 62:2026–2032.
31. Edinger AL, Clements JE, Doms RW. Chemokine and orphan receptors in HIV-2 and SIV tropism and pathogenesis. Virology 1999; 260:211–221.
32. Harouse JM, Bhat S, Spitalnik SL, Laughlin M, Stefano K, Silberberg DH, et al
. Inhibition of entry of HIV-1 in neural cell lines by antibodies against galactosyl ceramide. Science 1991; 253:320–323.
33. Yahi N, Baghdiguian S, Moreau H, Fantini J. Galactosyl ceramide (or a closely related molecule) is the receptor for human immunodeficiency virus type 1 on human colon epithelial HT29 cells. J Virol 1992; 66:4848–4854.
34. Furuta Y, Eriksson K, Svennerholm B, Fredman P, Horal P, Jeansson S, et al
. Infection of vaginal and colonic epithelial cells by the human immunodeficiency virus type 1 is neutralized by antibodies raised against conserved epitopes in the envelope glycoprotein gp120. Proc Natl Acad Sci U S A 1994; 91:12559–12563.
35. Robinson WE Jr, Montefiori DC, Mitchell WM. Antibody-dependent enhancement of human immunodeficiency virus type 1 infection. Lancet 1988; i:790–794.
36. Homsy J, Meyer M, Tateno M, Clarkson S, Levy JA. The Fc and not the CD4 receptor mediates antibody enhancement of HIV infection in human cells. Science 1989; 244:1357–1360.
37. Hioe CE, Bastiani L, Hildreth JE, Zolla-Pazner S. Role of cellular adhesion molecules in HIV type 1 infection and their impact on virus neutralization. AIDS Res Hum Retroviruses 1998; 14:S124–S254.
38. Bounou S, Leclerc JE, Tremblay MJ. Presence of host ICAM-1 in laboratory and clinical strains of human immunodeficiency virus type 1 increases virus infectivity and CD4(+)-T- cell depletion in human lymphoid tissue, a major site of replication in vivo
. J Virol 2002; 76:1004–1014.
39. Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D, et al
. HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol 2008; 9:301–309.
40. Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, et al
. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A 2008; 105:7552–7557.
41. Levy JA. The transmission of AIDS: the case of the infected cell. JAMA 1988; 259:3037–3038.
42. Phillips DM, Bourinbaiar AS. Mechanism of HIV spread from lymphocytes to epithelia. Virology 1992; 186:261–273.
43. Kaizu M, Weiler AM, Weisgrau KL, Vielhuber KA, May G, Piaskowski SM, et al
. Repeated intravaginal inoculation with cell-associated simian immunodeficiency virus results in persistent infection of nonhuman primates. J Infect Dis 2006; 194:912–916.
44. Gupta P, Mellors J, Kingsley L, Riddler S, Singh MK, Schreiber S, et al
. High viral load in semen of human immunodeficiency virus type 1-infected men at all stages of disease and its reduction by therapy with protease and nonnucleoside reverse transcriptase inhibitors. J Virol 1997; 71:6271–6275.
45. Hollingsworth TD, Anderson RM, Fraser C. HIV-1 transmission, by stage of infection. J Infect Dis 2008; 198:687–693.
46. Atkins MC, Carlin EM, Emery VC, Griffiths PD, Boag F. Fluctuations of HIV load in semen of HIV positive patients with newly acquired sexually transmitted diseases. BMJ 1996; 313:341–342.
47. Halperin DT, Bailey RC. Male circumcision and HIV infection: 10 years and counting. Lancet 1999; 354:1813–1815.
48. Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, Puren A. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med 2005; 2:e298.
49. Coombs RW, Reichelderfer PS, Landay AL. Recent observations on HIV type-1 infection in the genital tract of men and women. AIDS 2003; 17:455–480.
50. Zhang Z, Schuler T, Zupancic M, Wietgrefe S, Staskus KA, Reimann KA, et al
. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 1999; 286:1353–1357.
51. Padian NS, van der Straten A, Ramjee G, Chipato T, de Bruyn G, Blanchard K, et al
. Diaphragm and lubricant gel for prevention of HIV acquisition in southern African women: a randomised controlled trial. Lancet 2007; 370:251–261.
52. Tachet A, Dulioust E, Salmon D, De Almeida M, Rivalland S, Finkielsztejn L, et al
. Detection and quantification of HIV-1 in semen: identification of a subpopulation of men at high potential risk of viral sexual transmission. AIDS 1999; 13:823–831.
53. Munch J, Rucker E, Standker L, Adermann K, Goffinet C, Schindler M, et al
. Semen-derived amyloid fibrils drastically enhance HIV infection. Cell 2007; 131:1059–1071.
54. Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen ISY. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 1990; 61:213–222.
55. Greco G, Fujimura SH, Mourich DV, Levy JA. Differential effects of human immunodeficiency virus isolates on beta-chemokine and gamma interferon production and on cell proliferation. J Virol 1999; 73:1528–1534.
56. Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1alpha, and MIP-1beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995; 270:1811–1815.
57. Agosto LM, Yu JJ, Dai J, Kaletsky R, Monie D, O'Doherty U. HIV-1 integrates into resting CD4+ T cells even at low inoculums as demonstrated with an improved assay for HIV-1 integration. Virology 2007; 368:60–72.
58. Siliciano JD, Siliciano RF. Latency and viral persistence in HIV-1 infection. J Clin Invest 2000; 106:823–825.
59. Moore JP, Kitchen SG, Pugach P, Zack ZA. The CCR5 and CXCR4 coreceptors: central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses 2004; 20:111–126.
60. Kwa D, Vingerhoed J, Boeser B, Schuitemaker H. Increased in vitro cytopathicity of CC chemokine receptor 5-restricted human immunodeficiency virus type 1 primary isolates correlates with a progressive clinical course of infection. J Infect Dis 2003; 187:1397–1403.
61. Singh A, Collman RG. Heterogeneous spectrum of coreceptor usage among variants within a dualtropic human immunodeficiency virus type 1 primary-isolate quasispecies. J Virol 2000; 74:10229–10235.
62. Shioda T, Levy JA, Cheng-Mayer C. Macrophage and T-cell line tropisms of HIV-1 are determined by specific regions of the envelope gp120 gene. Nature 1991; 349:167–169.
63. Saez-Cirion A, Pancino G, Sinet M, Venet A, Lambotte O. HIV controllers: how do they tame the virus? Trends Immunol 2007; 28:532–540.
64. Buchbinder SP, Katz MH, Hessol NA, O'Malley PM, Holmberg SD. Long-term HIV-1 infection without immunologic progression. AIDS 1994; 8:1123–1128.
65. Pantaleo G, Graziosi C, Fauci AS. New concepts in the immunopathogenesis of human immunodeficiency virus infection. N Engl J Med 1993; 328:327–335.
66. Romeria F, Gabriel MN, Margolis DM. Repression of human immunodeficiency virus type 1 through the novel cooperation of human factors YY1 and LSF. J Virol 1997; 71:9375–9382.
67. Levy JA. The search for the CD8+ cell anti-HIV factor (CAF). Trends Immunol 2003; 24:628–632.
68. Sheridan PL, Mayall TP, Verdin E, Jones KA. Histone acetyltransferases regulate HIV-1 enhancer activity in vitro. Genes Dev 2005; 11:3327–3340.
69. Sagot-Lerolle N, Lamine A, Chaix ML, Boufassa F, Aboulker JP, Costagliola D, et al
. Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. AIDS 2008; 22:1125–1129.
70. Espert L, Denizot M, Grimaldi M, Robert-Hebmann V, Gay B, Varbanov M, et al
. Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. J Clin Invest 2006; 116:2161–2172.
71. Zinkernagel RM, Hengartner H. T-cell-mediated immunopathology versus direct cytolysis by virus: implications for HIV and AIDS. Immunol Today 1994; 15:262–268.
72. McCune JM. The dynamics of CD4+ T-cell depletion in HIV disease. Nature 2001; 410:974–979.
73. Guadalupe M, Reay E, Sankaran S, Prindiville T, Flamm J, McNeil A, et al
. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 2003; 77:11708–11717.
74. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al
. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12:1365–1371.
75. Giorgi JV, Liu Z, Hultin LE, Cumberland WG, Hennessey K, Detels R. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. J Acquir Immune Defic Syndr 1993; 6:904–912.
76. Ascher MS, Sheppard HW. AIDS as immune system activation. II. The panergic imnesia hypothesis. J Acquir Immune Defic Syndr 1990; 3:177–191.
77. Grossman Z, Meier-Schellersheim M, Paul WE, Picker LJ. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med 2006; 12:289–295.
78. Sodora DL, Silvestri G. Immune activation and AIDS pathogenesis. AIDS 2008; 22:436–446.
79. Ameisen JC. Programmed cell death (apoptosis) and cell survival regulation: relevance to AIDS and cancer. AIDS 1994; 8:1197–1213.
80. Effros RB. Replicative senescence: the final stage of memory T cell differentiation? Curr HIV Res 2003; 1:153–165.
81. Estes JD, Gordon SN, Zeng M, Chahroudi AM, Dunham RM, Staprans SI, et al
. Early resolution of acute immune activation and induction of PD-1 in SIV-infected sooty mangabeys distinguishes nonpathogenic from pathogenic infection in rhesus macaques. J Immunol 2008; 180:6798–6807.
82. Silvestri G, Paiardini M, Pandrea I, Lederman MM, Sodora DL. Understanding the benign nature of SIV infection in natural hosts. J Clin Invest 2007; 117:3148–3154.
83. Brenchley JM, Paiardini M, Knox KS, Asher AI, Cervasi B, Asher TE, et al
. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 2008; 112:2826–2835.
84. Herbeuval JP, Shearer GM. HIV-1 immunopathogenesis: how good interferon turns bad. Clin Immunol 2007; 123:121–128.
85. Mandl JN, Barry AP, Vanderford TH, Kozyr N, Chavan R, Klucking S, et al
. Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med 2008; 14:1077–1087.
86. Kannangara S, DeSimone JA, Pomerantz RJ. Attenuation of HIV-1 infection by other microbial agents. J Infect Dis 2005; 192:1003–1009.
87. Almeida JR, Price DA, Papagno L, Arkoub ZA, Sauce D, Bornstein E, et al
. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J Exp Med 2007; 204:2473–2485.
88. Summerfield JA, Ryder S, Sumiya M, Thursz M, Gorchein A, Monteil MA, et al
. Mannose binding protein gene mutations associated with unusual and severe infections in adults. Lancet 1995; 345:886–889.
89. Mangano A, Rocco C, Marino SM, Mecikovsky D, Genre F, Aulicino P, et al
. Detrimental effects of mannose-binding lectin (MBL2) promoter genotype XA/XA on HIV-1 vertical transmission and AIDS progression. J Infect Dis 2008; 198:694–700.
90. Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, et al
. Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro
, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression. Proc Natl Acad Sci U S A 2008; 105:8718–8723.
91. Sheehy AM, Gaddis NC, Chol JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 2002; 418:646–650.
92. Sheehy AM, Gaddis NC, Malim MH. The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. Nat Med 2003; 9:1404–1407.
93. Ulenga NK, Sarr AD, Thakore-Meloni S, Sankale JL, Eisen G, Kanki PJ. Relationship between human immunodeficiency type 1 infection and expression of human APOBEC3G and APOBEC3F. J Infect Dis 2008; 198:486–492.
94. Chiu YL, Soros VB, Kreisberg JF, Stopak K, Yonemoto W, Greene WC. Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells. Nature 2005; 435:108–114.
95. Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski J. The cytoplasmic body component TRIM5α restricts HIV-1 infection in old world monkeys. Nature 2004; 427:848–853.
96. Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 2008; 451:425–430.
97. Varthakavi V, Heimann-Nichols E, Smith RM, Sun Y, Bram RJ, Ali S, et al
. Identification of calcium-modulating cyclophilin ligand as a human host restriction to HIV-1 release overcome by Vpu. Nat Med 2008; 14:641–647.
98. Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, et al
. A whole-genome association study of major determinants for host control of HIV-1. Science 2007; 317:944–947.
99. Konig R, Zhou Y, Elleder C, Diamond TL, Bonamy MC, Irelan JT, et al
. Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 2008; 135:49–60.
100. Brass AL, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, et al
. Identification of host proteins required for HIV infection through a functional genomic screen. Science 2008; 319:921–926.
101. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124:783–801.
102. Fust G, Ujhelyi E, Hidvegi T, Paloczi K, Mihalik R, Hollan S, et al
. The complement system in HIV disease. Immunol Invest 1991; 20:231–241.
103. Hart ML, Saifuddin M, Uemura K, Bremer EG, Hooker B, Kawasaki T, et al
. High mannose glycans and siliac acid on gp120 regulate binding of mannose-binding lectin (MBL) to HIV type 1. AIDS Res Hum Retroviruses 2002; 18:1311–1317.
104. Wada M, Wada NA, Shirono H, Taniguchi K, Tsuchie H, Koga J. Amino-terminal fragment of urokinase-type plasminogen activator inhibits HIV-1 replication. Biochem Biophys Res Commun 2001; 284:346–351.
105. Munch J, Standker L, Adermann K, Schulz A, Schindler M, Chinnadurai R, et al
. Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell 2007; 129:263–275.
106. Rodman TC, Lutton JD, Jiang S, Al-Kouatly HB, Winston R. Circulating natural IgM antibodies and their corresponding human cord blood cell-derived Mabs specifically combat the Tat protein of HIV. Exp Hematol 2001; 29:1004–1009.
107. Lobo PI, Schlegel KH, Yuan W, Townsend GC, White JA. Inhibition of HIV-1 infectivity through an innate mechanism involving naturally occurring IgM anti-leukocyte autoantibodies. J Immunol 2008; 180:1769–1779.
108. Gomez MB, Hildreth JEK. Antibody to adhesion molecule LFA-1 enhances plasma neutralization of human immunodeficiency virus type 1. J Virol 1995; 69:4628–4632.
109. Rizzuto CD, Sodroski JG. Contribution of virion ICAM-1 to human immunodeficiency virus infectivity and sensitivity to neutralization. J Virol 1997; 71:4847–4851.
110. Wang SK, Liang PH, Astronomo RD, Hsu TL, Hsieh SL, Burton DR, et al
. Targeting the carbohydrates on HIV-1: Interaction of oligomannose dendrons with human monoclonal antibody 2G12 and DC-SIGN. Proc Natl Acad Sci U S A 2008; 105:3690–3695.
111. Burton DR, Stanfield RL, Wilson IA. Antibody vs. HIV in a clash of evolutionary titans. Proc Natl Acad Sci U S A 2005; 102:14943–14948.
112. Salzwedel K, Smith ED, Dey B, Berger EA. Sequential CD4-coreceptor interactions in human immunodeficiency virus type 1 Env function: soluble CD4 activates Env for coreceptor-dependent fusion and reveals blocking activities of antibodies against cryptic conserved epitopes on gp120. J Virol 2000; 74:326–333.
113. Decker JM, Bibollet-Ruche F, Wei X, Wang S, Levy DN, Wang W, et al
. Antigenic conservation and immunogenicity of the HIV coreceptor binding site. J Exp Med 2005; 201:1407–1419.
114. Ahmad R, Sindhu ST, Toma E, Morisset R, Vincelette J, Menezes J, et al
. Evidence for a correlation between antibody-dependent cellular cytotoxicity-mediating anti-HIV-1 antibodies and prognostic predictors of HIV infection. J Clin Immunol 2001; 21:227–233.
115. Homsy J, Meyer M, Levy JA. Serum enhancement of human immunodeficiency virus (HIV) correlates with disease in HIV infected individuals. J Virol 1990; 64:1437–1440.
116. Morrow WJW, Isenberg DA, Sobol RE, Stricker RB, Kieber-Emmons T. AIDS virus infection and autoimmunity: A perspective of the clinical, immunological, and molecular origins of the autoallergic pathologies associated with HIV disease. Clin Immunol Immunopathol 1991; 58:163–180.
117. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392:245–252.
118. Donaghy H, Stebbing J, Petterson S. Antigen presentation and the role of dendritic cells in HIV. Curr Opin Infect Dis 2004; 17:1–6.
119. Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 2005; 23:275–306.
120. Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, et al
. The nature of the principal type 1 interferon-producing cells in human blood. Science 1999; 284:1835–1837.
121. Schmidt B, Scott I, Whitmore RG, Foster H, Fujimura S, Schmitz J, et al
. Low-level HIV infection of plasmacytoid dendritic cells: onset of cytopathic effects and cell death after PDC maturation. Virology 2004; 329:280–288.
122. Soumelis V, Scott I, Gheyas F, Bouhour D, Cozon G, Cotte L, et al
. Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients. Blood 2001; 98:906–912.
123. Killian MS, Fujimura S, Hecht FM, Levy JA. Similar changes in plasmacytoid dendritic cell and CD4+ T cell counts during primary HIV-1 infection and treatment. AIDS 2006; 20:1247–1252.
124. Malleret B, Maneglier B, Karlsson I, Lebon P, Nascimbeni M, Perie L, et al. Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I IFN and immune suppression
2008. [Epub ahead of print].
125. Kottilil S, Shin K, Planta M, McLaughlin M, Hallahan CW, Ghany M, et al
. Expression of chemokine and inhibitory receptors on natural killer cells: effect of immune activation and HIV viremia. J Infect Dis 2004; 189:1193–1198.
126. Martin MP, Qi Y, Gao X, Yamada E, Martin JN, Pereyra F, et al
. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat Genet 2007; 39:733–740.
127. Godfrey DI, Kronenberg M. Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 2004; 114:1379–1388.
128. Moser B, Brandes M. Gammadelta T cells: an alternative type of professional APC. Trends Immunol 2006; 27:112–118.
129. Norris PJ, Moffett HF, Yang OO, Kaufmann DE, Clark MJ, Addo MM, et al
. Beyond help: direct effector functions of human immunodeficiency virus type 1-specific CD4+ T cells. J Virol 2004; 78:8844–8851.
130. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, et al
. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T-cells. Blood 2006; 107:4781–4789.
131. Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, et al
. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997; 278:1447–1450.
132. Kalams SA, Buchbinder SP, Rosenberg ES, Billingsley JM, Colbert DS, Jones NG, et al
. Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection. J Virol 1999; 73:6715–6720.
133. Guidotti LG, Ando K, Hobbs MV, Ishikawa T, Runkel L, Schreiber RD, et al
. Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice. Proc Natl Acad Sci U S A 1994; 91:3764–3768.
134. Khana KM, Lepisto AJ, Hendricks RL. Immunity to latent viral infection: many skirmishes but few fatalities. Trends Immunol 2004; 25:230–234.
135. Iversen AC, Norris PS, Ware CF, Benedict CA. Human NK cells inhibit cytomegalovirus replication through a noncytolytic mechanism involving lymphotoxin-dependent induction of IFN-beta. J Immunol 2005; 175:7568–7574.
136. Ogg GS, Jin X, Bonhoeffer S, Dunbar PR, Nowak MA, Monard S, et al
. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 1998; 279:2103–2106.
137. Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, Moodley E, et al
. CD8(+) T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 2007; 13:46–53.
138. Lieberman J. Tracking the killers: how should we measure CD8 T cells in HIV infection? AIDS 2004; 18:1489–1493.
139. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al
. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006; 443:350–354.
140. Trautmann L, Janbazian L, Chomont N, Said EA, Wang G, Gimmig S, et al
. Upregulation of PD-1 expression on HIV-specific CD8 + T cells leads to reversible immune dysfunction. Nat Med 2006; 12:1198–1202.
141. Price DA, Goulder PJR, Klenerman P, Sewell AK, Easterbrook PJ, Troop M, et al
. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc Natl Acad Sci U S A 1997; 94:1890–1895.
142. Yang OO. Aiming for successful vaccine-induced HIV-1-specific cytotoxic T lymphocytes. AIDS 2008; 22:325–331.
143. Kinter AL, Hennessey M, Bell A, Kern S, Lin Y, Daucher M, et al
. CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med 2004; 200:331–343.
144. Chougnet CA, Shearer GM. Regulatory T cells (Treg) and HIV/AIDS: summary of the September 7–8, 2006 Workshop. AIDS Res Hum Retroviruses 2007; 23:945–952.
145. Kornfeld C, Ploquin MJ, Pandrea I, Faye A, Onanga R, Apetrei C, et al
. Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS. J Clin Invest 2005; 115:1082–1091.
146. Smith TR, Kumar V. Revival of CD8+ Treg-mediated suppression. Trends Immunol 2008; 29:337–342.
147. Shearer GM, Clerici M. Protective immunity against HIV infection: has nature done the experiment for us? Immunol Today 1996; 17:21–24.
148. Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, et al
. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 382:722–725.
149. Kebba A, Kaleebu P, Serwanga J, Rowland S, Yirrell D, Downing R, et al
. HIV type 1 antigen-responsive CD4+ T-lymphocytes in exposed yet HIV type 1 seronegative Ugandans. AIDS Res Hum Retroviruses 2004; 20:67–75.
150. Rowland-Jones SL, McMichael A. Immune responses in HIV-exposed seronegatives: have they repelled the virus? Curr Opin Immunol 1995; 7:448–455.
151. Scott-Algara D, Truong LX, Versmisse P, David A, Luong TT, Nguyen NV, et al
. Increased NK cell activity in HIV-1 exposed but uninfected Vietnamese intravascular drug users. J Immunol 2003; 171:5663–5667.
152. Jennes W, Verheyden S, Demanet C, Adje-Toure CA, Vuylsteke B, Nkengasong JN, et al
. Cutting edge: resistance to HIV-1 infection among African female sex workers is associated with inhibitory KIR in the absence of their HLA ligands. J Immunol 2006; 177:6588–6592.
153. Devito C, Broliden K, Kaul R, Svensson L, Johansen K, Kiama P, et al
. Mucosal and plasma IgA from HIV-1-exposed uninfected individuals inhibit HIV-1 transcytosis across human epithelial cells. J Immunol 2000; 165:5170–5176.
154. Miyazawa M, Lopalco L, Mazzotta F, Lo Caputo S, Veas F, Clerici M. Factors modulating susceptibility to HIV infection: the “immunological advantage” of HIV-exposed seronegative individuals
2009 (in press).
155. Stranford S, Skurnick J, Louria D, Osmond D, Chang S, Sninsky J, et al
. Lack of infection in HIV-exposed individuals is associated with a strong CD8+ cell noncytotoxic anti-HIV response. Proc Natl Acad Sci U S A 1999; 96:1030–1035.
156. Burgener A, Boutilier J, Wachihi C, Kimani J, Carpenter M, Westmacott G, et al
. Identification of differentially expressed proteins in the cervical mucosa of HIV-1-resistant sex workers. J Proteome Res 2008; 7:4446–4454.
157. McNeely TB, Dealy M, Dripps DJ, Orenstein JM, Eisenberg SP, Wahl SM. Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro
. J Clin Invest 1995; 96:456–464.
158. Levy JA. HIV research: a need to focus on the right target. Lancet 1995; 345:1619–1621.
159. Sarkar I, Hauber I, Hauber J, Buchholz F. HIV-1 proviral DNA excision using an evolved recombinase. Science 2007; 316:1912–1915.
160. Levy JA. What can be achieved with an HIV vaccine? Lancet 2001; 357:223–224.
161. Hoover EA, Mullins JI, Chu HJ, Wasmoen TL. Development and testing of an inactivated feline leukemia virus vaccine. Semin Vet Med Surg (Small Anim) 1995; 10:238–243.
162. Uhl EW, Heaton-Jones TG, Pu R, Yamamoto JK. FIV vaccine development and its importance to veterinary and human medicine: a review FIV vaccine 2002 update and review. Vet Immunol Immunopathol 2002; 90:113–132.
163. van de Wijgert JH, Shattock RJ. Vaginal microbicides: moving ahead after an unexpected setback. AIDS 2007; 21:2369–2376.
164. Cohen MS, Gay C, Kashuba AD, Blower S, Paxton L. Narrative review: antiretroviral therapy to prevent the sexual transmission of HIV-1. Ann Intern Med 2007; 146:591–601.
165. Levy JA, Ziegler J. Acquired immune deficiency syndrome (AIDS) is an opportunistic infection and Kaposi's sarcoma results from secondary immune stimulation. Lancet 1983; ii:78–81.
166. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 2004; 4:762–774.