Primary HIV infection (PHI) is characterized by a transient symptomatic illness (in 40–90% of cases) associated with high levels of virus replication. In the large majority (>80%) of infected individuals, the transmitted virus results from the infection of a single virus variant as revealed by genome analysis of viral RNA isolated during PHI . Symptoms are not specific to HIV but typical of an acute viral syndrome and may include fever, fatigue, rash, headache, lymphadenopathy, pharyngitis, myalgia, arthralgia, aseptic meningitis, retrorbital pain, weight loss, depression, gastrointestinal distress night sweats, and oral or genital ulcers . The symptomatic phase generally lasts for 2–4 weeks in individuals with ‘normal’ rate of diseases progression, whereas severe and prolonged symptoms are associated with rapid disease progression [3,4]. Once chronic HIV infection is established, the course of HIV disease and progression may be influenced substantially by host (genetic and immunological) and virological factors . At present, there have not been reports of spontaneous, that is, immunologically driven, clearance of HIV following infection. However, a small percentage (1–5% based on case definition) of HIV-infected individuals experience stable disease, that is, lack of decline of CD4 T-cell counts, and control of virus replication below 1000 HIV RNA copies/ml for an extended period of time (at least 7–10 years) in the absence of antiretroviral therapy (ART) . These individuals are called long-term nonprogressors (LTNPs) . Furthermore, an even smaller percentage (<1%) of individuals show control of virus replication below 50 HIV RNA copies/ml regardless of the length of the time of control and are called elite controllers . Rarely, the control of virus replication in LTNPs can be explained by the presence of defective virus , and most of them are infected with replication-competent virus, thus indicating that host factors predominantly contribute to virus control and prevention of disease progression.
KINETICS OF IMMUNE RESPONSE DURING PRIMARY INFECTION
In order to discuss the kinetics of the different components of the immune response elicited by HIV infection, we will use as a reference the Stages defined by Fiebig on the basis of the kinetics of HIV viral RNA and the appearance of an HIV-specific antibody response [9,10].
Of particular importance is the initial period of infection defined by the so-called ‘eclipse phase’. This phase last for 10 days and defines the period when the virus is not detectable in the plasma [1,11]. Studies performed in rhesus macaques infected with simian immunodeficiency virus (SIV) [12,13] have been instrumental to delineate the events occurring in the ‘eclipse phase’. Virus-infected cells cannot be detected in the mucosa until 1–3 days after infection and the first infected cells are resting memory CD4 T cells expressing CCR5. In addition, submucosal dendritic cells and Langerhans cells uptake the virus from the mucosa through C-type lectins such as DC-SIGN [14,15], which binds HIV gp120 with high affinity [14,15] and internalizes virions and subsequently expresses them on the cell surface after the dendritic cells have matured and migrated to draining lymph nodes where they encounter T cells [14,16–18]. At 1 week postinfection, that is versus the end of the ‘eclipse period’, the virus becomes detectable in the draining lymph nodes where virus production may be amplified as result of spreading of infection among activated T cells that have come in contact with dendritic cells [19,20]. The environment of the lymphoid tissue is ideal for virus replication and spreading due to the large concentration of activated T cells, to the trapping of virions on the extracellular surface of follicular dendritic cells [21–23], and to the abundant production of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, or tumor necrosis factor α (TNF-α) that highly support HIV replication . The immune response to HIV at the end of the ‘eclipse phase’ is stimulated as indicated by the detection of proteins of the acute phase, by the initial detection of inflammatory cytokines resulting from the activation of the innate immune response [24–26], and likely by the stimulation of HIV-specific CD4 T cells. During the ‘eclipse phase’, no effector components of the immune response to HIV capable of containing the initial spreading of infection appear to be operational and after the amplification of the infection in the draining lymph nodes, HIV viral RNA becomes detectable in the plasma (Feibig Stage I) and spreading of the infection to other anatomic compartments such as the gut-associated lymphoid tissues (GALTs) occurs . At the end of the ‘eclipse phase’, HIV begins to spread to the GALT that is predominantly populated of CD4 CCR5+ memory T cells. This results in an exponential expansion of infection, with up to 20% of gut resident CD4 T cells being infected and 80% depleted [27–31]. The large depletion of CD4 T cells occurring in the lymphoid tissues during this stage is indicated by the detection of a number of markers of apoptosis such as TRAIL, microparticles containing CCR5, TNFR2, and soluble FAS ligand as viremia increases . By week 3–4, the levels of viremia peak (generally >107 virus particles per ml of plasma)  and it is just at this time that antibody response becomes detectable.
The first wave of antibody response is predominantly composed of anti-gp41 IgG antibodies, which form immune complexes with HIV virions . Immune complexes have been found in the large majority of individuals (90%) during PHI, but only a minority (about 20%) of virions was opsonised by anti-gp41 antibodies and forming immune complexes . The anti-gp41 antibodies bind both infectious and noninfectious virions and lack neutralizing activity . Anti-gp120 antibodies represent a minor component of the antibody response during PHI while become the dominant anti-Env antibody response after the transition to the chronic phase of infection. As viremia peaks and following initial decline, antibodies specific to the other HIV proteins such as Gag are detected by week 3–4 of infection (Feibig Stages III/IV). Taken together, the above observations indicate that the antibody response during PHI has no efficacy in the containment of HIV replication and spreading.
HIV-specific CD8 T-cell response is detected during the increase in viremia levels and generally peaks 1–2 weeks after viremia peak and the peak in CD8 T-cell response coincides with the decline in viremia levels [34,35]. The first wave of CD8 T-cell response is directed predominantly against Env and Nef HIV proteins. The initial CD8 T-cell response appears to have limited or no effect on HIV replication as indicated by the persistence of a homogeneous founder virus without evidence of immune-driven selection of virus escape mutants . It is only at the time of the peak CD8 T-cell response and the decline of viremia that numerous amino acid mutations occur in epitopes of the founder virus recognized by CD8 T cells . No mutations are observed in the escape mutants . The initial CD8 T-cell response is associated with a massive expansion of HIV-specific CD8 T cells . Despite the massive expansion, the initial CD8 T-cell response has likely limited efficacy in the control of virus replication because of the rapid emergence of virus escape mutants and of the rapid disappearance of the responding CD8 T-cell clones due to the lack of recognition of the escape mutants or of exhaustion resulting from high virus/Ag load [36,38].
In the absence of ART, the levels of viremia start to decline around week 4 after infection in order to reach the ‘virologic’ set point generally 12–16 weeks after infection, which marks the transition of the infection to the chronic phase . The contribution of the immune response to the decline of viremia is only partial and predominantly mediated by HIV-specific cytotoxic CD8 T cells that may kill HIV-infected CD4 T cells. However, a major mechanism of the decline may be the lack of cell targets, that is, CD4 T cells, for HIV due to the large depletion of CD4 T cells through direct virus cythopathic effect, killing by CD8 T cells and activation-induced cell death. There is no evidence that the antibody response plays any role in the partial suppression of the decline of viremia and establishment of the ‘virologic’ set point.
Neutralizing antibodies against autologous virus are detected in a large proportion of HIV-infected individuals about 3 months after infection  and their appearance is associated with the emergence of mutations in the Env region [41,42]. Neutralizing antibodies with broad neutralizing activity are generated only in a minority (about 20%) of individuals and appear 2–4 years after infection, but there is no evidence of their efficacy in the control of viremia [43–45]. The number of human antibodies with a broad neutralizing activity against a wide range of virus isolates [46–53] remains limited and the majority of neutralizing antibodies has narrow breadth .
Numerous phenotypical and functional abnormalities of the B-cell compartment have been described in HIV-infected individuals . These abnormalities include abnormal B-cell activation , appearance of transitional immature B cells and exhausted B cells [57,58], and progressive loss of recall responses to vaccination .
Passive administration of neutralizing antibodies in nonhuman primates showed protection against SIV challenge, but was dependent upon the titer and the quality of the antibodies [60,61]. In particular, the injection of a cocktail of neutralizing antibodies was able to prevent SIV infection after mucosal virus challenge [62–67]. However, B-cell depletion in monkeys with chronic SIV infection does not influence the levels of plasma viremia , thus suggesting that B cells have limited protective role during chronic infection.
Slow progression of HIV disease has been found to be associated with high titers of anti-p24 antibodies , with neutralizing antibodies directed against autologous virus , or with antibodies against certain gp120 epitopes . Antibodies with broader neutralizing activity have been found more frequently in LTNPs [72–76]. However, it is unclear whether these antibody responses reflect mechanisms of protection or rather the integrity of the immune system in LTNPs.
Finally, mucosal HIV-specific immunoglobulin A (IgA) response has been detected in HIV-exposed uninfected individuals . These IgA may prevent potentially HIV transcytosis through the epithelium . IgA antibodies specific for the gp120-CD4-binding site have also been detected in LTNPs .
THE ROLE OF CD8 T-CELLS IN VIRUS CONTROL
CD8 T cells play a critical role in antiviral immunity [34,35,80–84]. There are a number of observations underscoring the importance of HIV-specific CD8 T cells in the control of virus replication and prevention of disease progression in HIV-infected individuals. These include the rapid loss of control of virus replication after CD8 T-cell depletion in SIV-infected monkeys [80,81,85], the decline of viremia during PHI coinciding with the peak of CD8 T-cell response , the presence of CD8 T-cell responses in exposed uninfected individuals [86–89], and the association between protection and HIV-specific CD8 T-cell responses restricted by certain human leukocyte antigen (HLA) class I alleles [90,91].
CD8 T-cell responses from elite controllers compared to progressors have superior capacity to secrete multiple cytokines and chemokines (polyfunctionality), particularly IL-2 , to proliferate , to inhibit HIV replication in vitro and kill target cells [83,94], to express perforin and degranulate upon HIV-specific stimulation [95–98], and to target Gag epitopes [99,100]. CD8 T-cell responses from elite controllers also inhibited HIV replication without prior activation in vitro, thus suggesting the presence of a pool of CD8 T cells with immediate or rapidly inducible antiviral effector function [92,101–105]. Efficient viral suppression in vitro is predominantly mediated by CD8 T cells specific to Gag rather than Env or Nef [106,107], consistently with the observed protection associated with Gag-specific CD8 T-cell responses detected ex vivo.
THE ROLE OF CD4 T-CELLS IN VIRUS CONTROL
Memory CD4 T cells are the primary targets of HIV , and massive depletion of CD4 T cells, particularly of HIV-specific CD4 T cells , occurs during PHI. Long-term ART only partially restores the pool of total and HIV-specific memory CD4 T cells [27,28,110,111].
HIV-specific CD4 T cells harbor a skewed functional profile associated with a reduced IL-2 production and proliferation capacity [95,112,113]. This functional impairment was later associated with the expression of coinhibitory molecules [programmed death 1 [114–116], cytotoxic T lymphocyte antigen 4 (CTLA-4) ]. Interestingly, a recent study highlighted the functional impairment of follicular helper T cells (Tfh) as responsible for inadequate B-cell help, which may explain some of the functional abnormalities in the B-cell functions observed in HIV infection [118▪▪]. In this regard, it has been recently shown that Tfh serve as the major cell reservoir for HIV, which, in turn, may be responsible for their functional impairment [119▪▪].
Several evidence underscore the importance of CD4 T-cell responses in the control HIV . These include the enrichment in LTNPs and elite controllers of polyfunctional HIV-specific CD4 T cells and preservation of proliferation capacity [84,121–125], the greater production of IL-21 by HIV-specific CD4 T cells in HIV controllers [126,127], the presence of HIV-specific CD4 T cells with higher functional avidity and T-cell receptor-binding affinity in LTNPs , the association of some HLA class II alleles with lower viral loads [129,130], and the lower expression of CTLA-4 and other exhaustion markers in HIV-specific CD4 T cells in LTNPs .
The superior efficacy of CD8 T cells from elite controllers might also reflect the preservation of the CD4 TCM-cell compartment and of proliferation capacity, which was observed in elite controllers as compared to untreated and treated chronically HIV-infected individuals [121,122,128,131].
In addition, CD4 T cells from elite controllers do not show signs of immune exhaustion such as loss of polyfunctionality and expression of coinhibitory molecules [117,132]. Therefore, these cells are able to secrete IL-2, IL-21, and possibly other cytokines needed to help CD8 T cells in developing and maintaining their effector functions as well as their proliferation capacity and survival [101,121,122,133].
THE ROLE OF HLA ALLELES IN CONTROL
Whole-genome analysis has demonstrated that the genetic factors most strongly associated with nonprogressive infection are HLA class I alleles and the activating killer cell Ig-like receptor (KIR) allele KIR3DS [90,134–141]. In particular, the HLA-B*5701, HLA-B*5801, and the HLA-B*2705 are associated with slow disease progression, whereas HLA-B*35 with faster disease progression [139,142]. Protective CD8 T-cell responses restricted by HLA-B*5701 and HLA-*B27 recognize the following immunodominant Gag epitopes: TSTLQEQIGW (TW10), KAFSEPVIPMF (KF11), ISPRTLNAW (IW9) restricted by HLA-B*5701, and KRWIILGLNK (KK10) restricted by HLA-B*27 [138,143]. The low viremia is associated with high rate of sequence mutation (reflecting the immunological pressure exerted on epitopes restricted by HLA-B*57), induction of virus variants with reduced replication capacity, and the ability to recognize epitopes with escape mutations [144,145]. The effect of HLA-B on disease outcome seems to be mediated in part by the amino acid position located in the peptide-binding groove, suggesting a difference in the conformation of the peptide presentation . Indeed, intrinsic differences in self-peptide binding among HLA molecules are important during T-cell repertoire development. As fewer self-peptides are able to bind to HLA-B*57 molecules, fewer CD8 T cells restricted by this HLA will undergo negative selection. HLA-B*57-restricted CD8 T cells have higher tolerability for epitope mutations: several mutations in the peptide recognized do not abrogate the recognition capacity by T cells. These observations explain also the association between HLA-B*57 and control of hepatitis C virus (HCV) infection and the association between HLA-B*57 and HLA-B*27 and enhanced risk of autoimmunity [146–148]. Along the same line, KK10-specific CD8 T-cell clones isolated from elite controllers expressing HLA-B*27 were characterized by complementarity determining regions 3 (CDR3) sequences significantly closer to germline sequences, superior ability to control virus replication in vitro, and superior cross-reactivity than KK10-specific CD8 T-cell clones isolated from progressors .
HIV-specific T-cell and antibody responses have been extensively characterized in HIV infection. Despite the fact that the magnitude of these responses is orders of magnitude greater as compared to those elicited by other viruses establishing chronic infections, HIV-specific responses fail to effectively control HIV replication and disease progression in the absence of ART in the large majority (>95%) of HIV-infected individuals. Several genetic factors and functional profile of the HIV-specific immune response (particularly in the T-cell response) are associated with protection in LTNPs and elite controllers. These observations together with the recent identification of Tfh cells as the major cell reservoir for HIV infection may guide the future development of therapeutic interventions aimed at the development of strategies that may either stimulate effective T-cell immunity or efficiently target the major HIV cell reservoir, that is, Tfh cells.
Conflicts of interest
The authors declare no conflict of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 357–359).
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