Share this article on:

CD8+ T cells in preventing HIV infection and disease

McDermott, Adrian B.; Koup, Richard A.

doi: 10.1097/QAD.0b013e328353bcaf
Special Reviews

The complex interplay between the host immune response and HIV has been the subject of intense research over the last 25 years. HIV and simian immunodeficiency virus (SIV) CD8+ T cells have been of particular interest since they were demonstrated to be temporally associated with reduction in virus load shortly following transmission. Here, we briefly review the phenotypic and functional properties of HIV-specific and SIV-specific CD8+ T-cell subsets during HIV infection and consider the influence of viral variation with specific responses that are associated with disease progression or control. The development of an effective HIV/AIDS vaccine combined with existing successful prevention and treatment strategies is essential for preventing new infections. In the context of previous clinical HIV/AIDS vaccine trials, we consider the challenges faced by therapeutic and vaccine strategies designed to elicit effective HIV-specific CD8+ T cells.

Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Correspondence to Adrian B. McDermott, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA. E-mail:

Received 29 February, 2012

Accepted 15 March, 2012

Back to Top | Article Outline


The complex relationship between HIV and the host immune response has been the subject of intense research over the last 25 years and has revealed much about the balance between adaptive immune responses and control of virus replication. However, it remains unclear whether these studies reveal what is required by a HIV vaccine in order to control viral replication after challenge. Here we shall review the role of antigen-specific CD8+ T cells in HIV and simian immunodeficiency virus (SIV) infection, their intimate relationship with virus evolution and relevant in-vitro data and highlight recent advances in vectored vaccine challenge studies in non-human primates (NHPs). The advances represented by these studies may give an indication of how to develop interventions to reduce acquisition of HIV and control virus burden in the most affected populations. Because approximately 34 million individuals are currently living with HIV, and a further 7400 are infected daily [1], preventing new infections will be critical to curtailing the epidemic ([2], this issue). Although some interventions have impacted the transmission rate, such as male circumcision, antiretroviral treatment and vaginal microbicides [3–6], they offer incomplete protection from HIV acquisition.

Back to Top | Article Outline

Steps in HIV infection

Transmission of HIV occurs predominantly via a mucosal route through sexual contact, although direct exposure through the skin (needle stick or intravenous drug use) is not uncommon. HIV RNA remains undetectable for up to 10 days (the eclipse phase), after which, a high viremia of several million RNA copies (Fig. 1) results in extensive systematic depletion of resting CD4+ T cells lacking activation markers, particularly those in the gut mucosa [7,8]. Establishment of a latent reservoir of infected cells in lymphatic tissues is associated with the general infection of CD4+ T cells [9]. The majority of HIV infections proceed to a chronic phase with steady-state virus loads of 10–50 × 103 RNA copies/ml. Asymptomatic chronic HIV infection can last 3–20 years depending upon the occurrence of opportunistic infections in the face of declining host CD4+ T-cell numbers [10]. In order to reliably prevent systemic infection and establish a latent reservoir, vaccine-elicited immune responses or other interventions must act prior to or during the eclipse phase of HIV replication (Fig. 1) [7,11]. Some rare individuals demonstrate spontaneous control of HIV or SIV replication (Fig. 2) [12,13]. In a minority of cases (0.5%), the chronic phase of HIV infection is characterized by low viral loads (5–15 × 103 RNA copies/ml) and stable CD4+ T-cell counts. An even smaller group of individuals maintain virtually undetectable HIV replication (<50 copies of HIV RNA copies/ml) for many years after infection [13]. Although all of these individuals are known as long-term nonprogressors (LTNPs), those with undetectable virus loads are known as ‘elite controllers’ [13,14]. Some of these individuals are quite clearly infected with defective versions of HIV [15]; yet, most are infected with replication-competent HIV [16,17] that continue to replicate and gradually evolve over the course of infection [18,19]. Here, we shall highlight as well the contribution of the CD8+ T-cell response in the maintenance or establishment of elite control of virus replication.

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Back to Top | Article Outline

CD8+ T-cell subpopulations

Cytotoxic CD8+ T cells recognize and destroy cells that express ‘nonself’ or ‘foreign’ peptide in the context of major histocompatibility complex (MHC) class I molecules on the surface of nucleated cells. These MHC molecules are also known as human leukocyte antigens (HLAs). Long-lasting CD8+ T-cell-mediated immunity to a particular intracellular pathogen requires the establishment of a memory cell pool that proliferates rapidly in response to antigen re-encounter. Although the precise mechanisms of CD8+ T-cell differentiation pathways remain to be fully elucidated, the heterogeneity in T-cell populations demonstrates patterns that can be used to distinguish functional stages of the immune response.

Populations of T cells are subdivided by activation markers (CD45RA and CD45RO), elements required for co-stimulation of CD8+ T-cell (CD27 and CD28), regulation (PD-1), trafficking (CD11a, CD62L, α4β7), chemokine and cytokine secretion [interferon (IFN)γ, IL2, tumor necrosis factor (TNF)α, CCL3] or chemokine and cytokine secretion receptors (CD127, CD25, CCR7). In addition, other distinctions include functional molecules (granzymes, perforin), markers of late differentiation (CD57, KLRG1) or intracellular signaling molecules (mTOR and T-Bet). Classically, viral infection leads to an expansion of a population of effector CD8+ T cells coming from the naive T-cell (CD45RA+, CCR7+) pool. Following infection, these effector cells eventually contract by 95% to leave a heterogeneous pool of dedicated antigen-specific CD8+ T-memory cells [20,21]. Short-lived effector CD8+ T cells have a high expression of perforin and granzyme molecules and migrate out of the lymphoid tissue and kill infected target cells in the periphery [22].

Although there are commonalities between the differentiation patterns of antigen-specific CD8+ T cells, viral specificity can affect the combination and timing of markers, for example, during a chronic viral infection such as HIV (Table 1). Shortly following infection, the memory pool of cells is established that is divided into at least two subsets (Table 1): central memory CD8+ T cells (Tcm cells), that remain in lymphoid tissue, express high levels of IL2 and the homing markers CD62L and CCR7; and effector memory CD8+ T cells (Tem cells) that are found in spleen, liver and mucosal tissue and express low levels of IL2 and CD62L. They are loaded with perforin and granzyme and secrete IFNγ to enable them to perform immediate effector functions [23,24]. With antigen-specific Tcm associated with rapid proliferation, viral clearance and HIV long-term non-progression, it was assumed that they would be the essential component elicited by an efficacious HIV vaccine [25–28]. Although CD8+ Tcm cells are superior in proliferation, expansion and migration, leading to a robust anemnastic response, they are less able than Tem cells to direct immediate effector functions. Therefore, they have a kinetic disadvantage that could enable HIV to establish infection at the portal of entry [29–31]. Importantly, early virus control mediated by Tem cells resident in peripheral lymphoid and mucosal tissue does not preclude the eventual expansion and migration of multifunctional antiviral effector cells generated from the Tcm cells pool [31].

Table 1

Table 1

Back to Top | Article Outline

CD8+ T cells in HIV infection

Over the last two decades, a role for CD8+ T-cell-mediated immunity in reducing HIV replication and retarding the onset of disease has been established [32–41]. The rapid containment of primary HIV viremia implicated antigen-specific adaptive immune responses. An initial indication that CD8+ T cells could play a part in suppression of HIV-1 replication in vitro was shown in 1986 [42]. Ex-vivo studies subsequently demonstrated a causative link between a high frequency of circulating HIV-specific CD8+ T cells and reduction of HIV replication, which correlated with an improved clinical outcome in infected individuals [32–34,43]. Since the discovery in 1987 that SIV-infected NHPs induced a disease remarkably similar to that by HIV-1 [44], the relationship between lentivirus replication and the host cellular immune responses can be better studied [45–47]. Two complementary CD8+ T-cell depletion studies using Indian-origin rhesus macaques showed that SIV replication was controlled prominently by the presence of CD8+ T cells, in both the acute and chronic phases of infection. The experimental depletion of CD8+ T cells in NHP infected with pathogenic SIV demonstrated that absence of CD8+ T cells in the acute or chronic stages of infection resulted in a striking increase in virus replication and acceleration in disease progression [38,39]. Furthermore, in conditions in which rhesus macaques were suppressing SIV replication, either spontaneously (elite controller) or by previous infection with genetically modified live attenuated SIVs, transient depletion of CD8+ T cells resulted in increased virus burden that was brought back to baseline upon the restoration of the CD8+ T-cell compartment [36,37,48,49]. Discovery of a direct link between the adaptive T-cell responses and virus replication shortly after transmission of HIV gave hope to the notion that an HIV vaccine capable of controlling virus replication even in the absence of protection against infection was achievable. This observation was especially timely considering the failure of the AIDSVAX trial in 2003 to demonstrate protection against infection [50], ([132], this issue).

Back to Top | Article Outline

CD8+ T-cell–HIV interactions: virus escape

The possibility that T-cell-based HIV vaccine approaches might impact on virus control prompted intense investigation into the immune pressure exerted by CD8+ T cells. Sequence analyses of HIV and SIV following transmission and at peak viremia demonstrated homogeneity of populations consistent with a bottleneck at transmission, leading to the establishment of infection by only one or a few virus stains (called transmitted founder viruses) [51,52]. As we have described above, virus-specific CD8+ T-cell responses become maximal 7–14 days following the peak of viremia, and concurrent with the decline in virus replication (Fig. 2). However, lentivirus infections are notoriously mutable and, shortly after the CD8+ T-cell response is established, mutations in HIV or SIV start to accumulate corresponding to regions of CD8+ T-cell recognition (T-cell epitopes). Mutations in the epitopes have been found to negate binding of the peptide to the MHC class I molecule, alter recognition of the epitope by the T-cell receptor (TCR) or completely delete the CD8+ T-cell epitope [53–58]. These spontaneous mutations in the virus genome are termed ‘virus escape’ mutations. They are maintained by the selective pressure exerted by the CD8+ T cells [57,59–64], and occur rapidly in nonessential variable regions of the virus genome. Of note, CD8+ T-cell responses directed at more essential conserved regions of the virus genome often result in substantial fitness cost to the virus [65]. These mutations often lead to further changes outside the region recognized by the CD8+ T cells in order to compensate for the fitness cost to the virus [57,61,66–68]. In the absence of adequate compensatory mutations, some CD8+ T cell escape variants become so impaired that they are not maintained in the virus population [67–72]. So, during the early stages of infection, there is a large turnover of virus populations in an infected individual as a result of the interplay between CD8+ T cells and virus escape [73–75]. However, not all mutations in the early stages of infection are due to host CD8+ T-cell pressure; some may represent reversions when the virus is transmitted to a host in which the virus no longer finds itself under pressure from a CD8+ T-cell response that was present in the donor [67,68,76,77]. It has been reported that LTNPs commonly target epitopes located in conserved regions during initial or early infection and consequently exert better long-term control of virus replication [78–82]. This has the added benefit of limiting the replication capacity and further generation of other escape variants in the infecting HIV or SIV.

Back to Top | Article Outline

Host genetics and HIV control

Long-term control of HIV or SIV replication in elite controllers is greatly influenced by host genetics and potentially TCR clonotype repertoire shaped by the viral antigenic history in the individual [83,84]. The clearest association with control of HIV or SIV virus replication can be found at the HLA class I loci (or MHC for rhesus macaques) [84,85]. Control of HIV replication has been associated with the ability to mount a diverse class I restricted response, wherein HIV-infected individuals who are heterozygous at the HLA class I loci have slower disease progression [86]. Those individuals who demonstrate greatest control of HIV or SIV replication have an overrepresentation of HLA-B*27, HLA-B*5701, HLA-B*5703 and HLA-B*5801 alleles in humans and Mamu-A*01, Mamu-B*08 and Mamu-B*17 alleles in rhesus macaques [87–91]. There is also a suggestion that control of HIV infection by HLA-B*57 and HLA-B*27 is related to stronger natural killer cell responses mediated by KIR3DL1 [92,93], ([94], this issue). Although this relationship is not absolute in either HIV or SIV infection, these individuals are more likely to mount dominant and effective CD8+ T-cell responses that target constant regions of the virus. Control mediated by protective MHC alleles can be both tenuous and robust. For example, HIV-infected individuals expressing the HLA-B*27 alleles have the capability to mount effective CD8+ T-cell responses against the Gag-KK10263–272 epitope that is associated with control of viremia [95]. However, escape mutations can occur within the immunodominant Gag-KK10263–272 epitope late in the course of infection, resulting in virus breakthrough and advancement to disease [69,95–98].

In the NHP model, superinfection of Mamu-B*17 elite controlling rhesus macaques with an SIV engineered to eliminate all immunodominant Mamu-B*17 epitopes (essentially representing a pre-escaped virus) did not result in unabated control of viral replication as expected. This finding suggests that a broad subdominant CD8+ T-cell response might also play a role in the control of virus replication [99]. Further supporting this concept is the fact that escape from immunodominant responses in the chronic phase of virus replication does not always result in increased virus replication [99–103]. Furthermore, it has been demonstrated that elite controllers may have a low level of viremia and constant evolution of the virus population under pressure from multiple CD8+ T cells simultaneously [103]. The immunodominant Mamu-A*01 Gag-CM9181–189 epitope, like HLA-B*27-restricted Gag-KK10263–272, is found in a conserved region of Gag and has a role in the control of SIVmac239 replication in rhesus macaques. However, escape from this epitope does not always herald an increase in viral replication [101,104,105].

A public TCR-β clonotype is defined as a TCR-β amino acid sequence specific for a particular epitope/MHC that occurs in more than one individual and has been associated with efficient CD8+ T-cell responses [83]. Examination of the TCR clonotypes from CD8+ T cells specific for SIV Gag-CM9181–189 reveals that control of SIV infection is associated with the use of public TCR clonotypes [106]. Likewise, CD8+ T cells that recognize the HIV Gag-KK10263–272 epitope were associated with low virus loads, enriched for public TCR clonotypes, and had high avidity for the peptide/HLA complex [107,108]. Of note, when Gag-CM9181–189 was targeted by TCRs with a limited public repertoire, they failed to control virus replication following escape [105]. Consequently, the TCR repertoire of the responding CD8+ T-cell population can provide flexibility in recognizing escape variants and may strongly influence the ability of an individual to control HIV or SIV infection [109]. Overall, CD8+ T-cell-mediated control of SIV or HIV infection is influenced by an interplay between host-encoded MHC class I restriction and the TCR repertoire, the mutability of the viral epitopes targeted and the capacity of the virus to replicate and generate mutations. Although the magnitude of the CD8+ T-cell response probably contributes to viral control, a broad cellular antiviral response is more likely to be able to overcome viral mutations than a narrowly focused response [98,110].

Back to Top | Article Outline

CD8+ T cells and elite controllers

In addition to the specificity and antigen sensitivity of the CD8+ T-cell response described above, the ‘quality’ of the CD8+ T cells is also vital in the control of HIV replication (Table 2). In general, elite controllers have a greater frequency of HIV-specific CD8+ T cells, whereas a proportion have CD8+ T cells that can liberate multiple effector functions (crucially, the secretion of IL2), proliferate rapidly and upregulate perforin [111–116]. Recently, the in-vivo secretion of IL21 by HIV-specific CD8+ T cells from elite controllers has been linked with the maintenance of CD8+ cells and secretion of IL2 in the control of virus replication [117]. However, HIV-specific CD8+ T cells from HIV-infected progressors generally secrete fewer cytokines and chemokines (IFNγ or CCL3) and proliferate poorly [111]. Notably, maintenance of the cytotoxic potential of HIV-specific CD8+ T-cell populations in elite controllers has been correlated with rapid expansion, upregulation of the transcription factor T-bet and ability to mediate in-vitro suppression of HIV replication via granzyme B at low effector-to-target cell ratios [116,118–120]. Indeed, treatment of CD8+ T cells from HIV progressors ex vivo with phorbol myristate acetate and ionomycin restored the HIV-specific CD8+ T-cell proliferative capacity and cytotoxic potential in vitro. This finding suggests a defect in the ability of these cells to function in vivo [119].

Table 2

Table 2

An increase in regulatory T cells (CD4+, CD25+, FOXP3+, CD127dim) is associated with reduced proliferation of HIV-specific CD8+, HLA-DR+, CD38+ T cells [121] and advanced disease in vivo [122,123]. In this regard, elite control correlates with an unusually low level of Tregs, which is then associated with CD8+ T cells that maintain their ability to proliferate in the face of general immune activation [118,122]. Furthermore, proliferative capacity and lytic granule loading of CD8+ T cells restricted by ‘protective’ HLA-B*27 and HLA-B*57 alleles was not suppressed by Tregs compared with CD8+ T cells restricted by ‘nonprotective’ alleles, even in the same individual [120]. The programmed cell death molecule 1 (PD-1) is also associated with immunosuppressive (proliferation and cytokine production) but primarily regulates the ability of CD8+ T cells to survive [124,125]. Increased levels of PD-1 during HIV infection leading to exhaustion of HIV-specific CD8+ effector memory T cells (Tem: CD45RA+/−, CCR7, CD62Llo, CD28) have been reported, but elite controllers tend to have lower PD-1 expression and the functions of their CD8+ Tem cells are maintained [126,127]. However, the major determinants of CD8+ T-cell exhaustion are probably high viremia [128] and a limited TCR clonotype repertoire, as explained above [107,108].

We have briefly highlighted some important aspects of CD8+ T-cell immunobiology that are associated with control of HIV and more extensive reviews are available [129–131]. All of the studies demonstrate that multiple aspects of CD8+ T cells are associated with viral control. What remains elusive after two decades of research in this area is which specific CD8+ T-cell qualities, if present in vaccine-elicited CD8+ T cells, would assure optimum control of HIV during and after the eclipse phase following HIV transmission [7,11].

Back to Top | Article Outline

CD8+ T cells and vaccine development

The rational design of a vaccine requires a brief consideration of those viral proteins that have been associated with or have influenced control of virus replication in SIV and HIV infection ([132], this issue). The choice of vectored vaccine inserts to elicit CD8+ T-cell responses is often tempered by pragmatic considerations such as, construction and payload of the vector, as well as issues of stability and ease of manufacturing. The in-vitro and in-vivo experimental evidence suggests that Gag-specific responses in HIV and SIV infection are most strongly associated with control of virus replication in LTNPs [133–139]. Indeed, HIV Gag-specific CD8+ T-cell responses within large cohorts of HIV-infected adults, and more recently neonates, correlate with clinical outcome and control of virus replication irrespective of HLA. They relate directly to the number of Gag-specific T-cell epitopes targeted in the protein [110,135,136,140,141].

The Nef, Env and Tat proteins have shown negative correlations with virus control in large cohorts of HIV-infected individuals and SIV-infected rhesus macaques [135,136,142]. Thus, proteins that are expressed early in the replicative cycle of SIV or HIV would be premium targets for the immune response. In-vitro studies demonstrate that clones specific for Nef or Pol proteins recognize infected cells earlier than those targeting structural proteins [143,144]. The incoming virion may also provide sufficient Gag antigen to allow for alternative processing and presentation to CD8+ T cells, and therefore, Gag-specific CD8+ T cells potentially recognize infected cells even before they produce new viral proteins. This phenomenon is restricted to Gag, which is the predominant protein in virions [145], whereas Tat, Nef or Env proteins are less abundant [134]. Intriguingly, Sacha et al. [146] also demonstrated that Pol-specific CD8+ T cells recognize and eliminate infected cells around 6 h after infection. However, how this activity may affect in-vivo recognition is not clear considering that Gag expression is about 20-fold higher than Pol in infected cells [145]. Of potential importance, CD8+ T-cell pressure exerted on the Env protein results in reduced replicative capacity of HIV [147,148]. However, the CD8+ T-cell response to Env is rapidly eroded because Env is able to tolerate mutations more readily than Gag [149]. Moreover, consistent pressure upon more structurally and functionally constrained proteins by CD8+ T cells is associated with spontaneous control of HIV [82,83,149]. The best combination of proteins to include in HIV vaccines designed to elicit potent CD8+ T-cell antiviral responses can only really be determined by trial and error, a costly and inefficient system that may have, in part, contributed to the failure of the STEP vaccine trial. In the light of the STEP trial, recent approaches to vaccine design have emerged that seek to increase the number of epitopes recognized in constant regions of circulating virus strains [150,151]. These approaches employ in-silico analyses to design a variety of immunogens that include the most common sequences from circulating HIV isolates likely to be recognized by CD8+ T cells in acute and chronic infection [150–153]. Results of these approaches are promising and the first tests of HIV vaccine candidates based upon these immunogens are planned to enter phase I clinical trials shortly.

In September 2007, Merck and the HIV Vaccine Trials Network suspended the STEP phase IIb proof-of-concept vaccine trial prematurely because it failed to reach the interim criteria, but of most concern was the fact that the vaccine group was potentially at a greater risk of HIV acquisition [154,155]. This trial tested recombinant adenovirus 5 (rAd5) vectors that encoded consensus sequences from HIV-1 clade B Gag, Pol and Nef proteins delivered in a prime and boost regimen. This regimen had previously been shown to elicit persisting CD8+ T-cell responses of high magnitude (0.5–1% of circulating CD8+ T cells) in 73% of recipients after the full vaccination regimen [156]. However, the vaccine elicited meager CD8+ T-cell responses to each protein and targeted few highly conserved epitopes. Instead it targeted epitopes subject to variation in the Gag, Pol and Nef proteins. This response effectively reduced the coverage of potential epitopes and increased the likelihood of escape upon HIV infection [156,157]. Phenotypically, the CD8+ T-cell responses elicited by the STEP vaccine were more typical of HIV-infected individuals who progress to disease than those who control infection. Vaccine-induced CD8+ T cells had limited effector functions and quality and were confined to those that secreted IFNγ and TNFα, but seldom IL2. Vaccination with the Merck rAd5 vaccine vector has been associated with a reduction in vaccine-elicited CD4+ T-cell frequencies in individuals with prior exposure to naturally occurring adenoviruses. This was independent of whether vaccinees developed Gag-specific, Pol-specific or Nef-specific CD8+ T cells [156,158]. Recent work has demonstrated a close relationship between memory CD8+ T cells and CD4+ T cells, especially in persistent virus infections [159]. This finding may have important implications in designing future CD8+ T-cell vaccine strategies. Thus, despite eliciting a high magnitude of HIV Gag-specific, Pol-specific and Nef-specific CD8+ T cells, recipients of the STEP vaccine were as susceptible to infection as placebo controls [160]. Predictably, HIV-infected STEP vaccine recipients with HLA-B*27, HLA-B*57 and HLA-B*58 alleles had lower virus loads [160]. Failure of the STEP trial, although discouraging, did highlight the difficulties in designing and effectively delivering T-cell immunogens. Since the STEP trial results in 2007, the HIV vaccine field has started to reconsider HIV vaccines designed that elicit CD8+ T cells and have successfully focused more upon vaccines that stimulate neutralizing antibodies ([132], this issue). This effort has been buoyed by the unfolding analysis of immune correlates in the RV144 vaccine trial [161–163]. Nevertheless, despite the failure of the STEP trial, the use of a rhesus cytomegalovirus (rhCMV) vector, which elicits a different quality of a CD8+ T-cell response, has shown a dramatic ability to protect rhesus macaques against a stringent SIV challenge [164,165].

A number of replication-incompetent viral vectors have been developed as AIDS vaccines. These, when used alone or in heterologous prime–boost combinations [166], elicit high-frequency CD8+ T-cell responses to HIV/SIV epitopes [167–169]. Most of these regimens have been tested for the ability to protect rhesus macaques against SIV challenge. Typically, heterologous prime–boost regimens have demonstrated a reduction in peak and set point viral loads and even prolonged survival [167,170–173]. Since the development and implementation of the SIV repeated low-dose challenge model [51,174–176], a few vaccine regimens have significantly reduced virus load following stringent SIV challenge [177–179]. However, prime and boost immunization with replication-competent rhCMV vector led to profound viral control in approximately 50% (25/50) of rhesus macaques challenged with repeated low-dose mucosal SIVmac239 for up to 3 years following the last vaccination (Fig. 2). Most remarkable for the HIV vaccine field was the pattern of virus control in the rhesus macaques that received prime and boost with rhCMV vector. Control of virus replication was distinct and swift with the typical peak of virus production being reduced to a moderate short burst of virus replication followed by robust control signified by undetectable virus loads (Fig. 2). Some rhesus macaques demonstrated an occasional ‘blip’ in virus replication that was also rapidly controlled. Subsequent control of virus replication persisted with fewer episodes of virus ‘blips’ over time. Notable for this study was the complete absence of binding or neutralizing antibody, indicating that T cells were primarily responsible for the observed viral control.

Why was this vaccine so successful? Possibly because of its ability to elicit a high magnitude of effector memory T cells that could efficiently eliminate virally infected cells and prevent the establishment of chronic infection. Hansen et al. [165] have demonstrated that a rhCMV vector encoding the whole SIV proteome can elicit high-frequency CD8+ Tem cells in lymphoid and mucosal tissue, and these are associated with significant virus control. CMV is a potent inducer of persistently maintained CD4+ and CD8+ Tem [180]. As described above, CD8+ Tem cells retain the capability to rapidly proliferate, reside in peripheral lymphoid and mucosal tissue and exert early virus control [31]. Rhesus macaques immunized with rhCMV elicited approximately 40% more CD8+ Tem cells in the periphery over a year following the vaccine regimen compared with a DNA prime rAd5 boost immunization control rhesus macaque population [164,181]. Hence, replication-competent persistent infection with rhCMV encoding SIV genes offered a way to generate persistent high-frequency SIV-specific CD8+ T cells with a Tem cell bias. The latter would test the hypothesis that Tem cells can mediate control of SIVmac239 infection in a low-dose repeated challenge [164]. The SIV-specific CD8+ T-cell response was very broad and targeted epitopes that differed from those targeted by either SIV infection or vaccination with rAd5 encoding the exact same genes [182]. The presence of rhCMV vector-encoded genes, which potentially interfere with MHC class I processing and presentation, has been implicated in this unusual pattern of CD8+ T-cell responses [182]. Although this finding is still under investigation, it too is potentially important for designing CD8+ T-cell HIV vaccines.

The nature of the virus control elicited by the prototype rhCMV–SIV vector is major progress in the search for a HIV vaccine. However, although human CMV–HIV vectors are being developed and considered for clinical trials, the regulatory hurdles for this vector are arduous. Although most of us are persistently infected with CMV, primary infection in individuals who are pregnant or immunocompromised carries substantial risk or morbidity and mortality.

Back to Top | Article Outline


During the last 25 years, we have learned much about the phenotypic and functional characteristics of CD8+ T cells that are associated with control of acute and chronic HIV infection and found in elite controllers. Translation of this knowledge has not led to the development of an efficacious T-cell-based HIV vaccine. However, in-depth analyses of the failed STEP trial have revealed valuable data for designing future HIV vaccines. Inspiring results in the NHP efficacy model have demonstrated that using the rhCMV vector to elicit high frequencies of CD8+ Tem cells, in the absence of antibody, can give a precipitous and unprecedented level of SIV control in some animals. Despite these compelling data, further development of the human CMV–HIV vaccine strategy will be hampered by concerns associated with the safety profile of the vector. Yet, the principal of eliciting high-frequency CD8+ Tem has been well demonstrated.

Back to Top | Article Outline


Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline


1. WHO. http://
2. De Cock KM, Jaffe HW, Curran JW. The evolving epidemiology of HIV/AIDS. AIDS 2012; 26:1205–1213.
3. Shattock RJ, Warren M, McCormack S, Hankins CA. AIDS. Turning the tide against HIV. Science 2011; 333:42–43.
4. Karim SS, Karim QA. Antiretroviral prophylaxis: a defining moment in HIV control. Lancet 2011; 378:e23–e25.
5. Karim SS, Kashuba AD, Werner L, Karim QA. Drug concentrations after topical and oral antiretroviral preexposure prophylaxis: implications for HIV prevention in women. Lancet 2011; 378:279–281.
6. Excler JL, Rida W, Priddy F, Gilmour J, McDermott AB, Kamali A, et al. AIDS vaccines and preexposure prophylaxis: is synergy possible?. AIDS Res Hum Retroviruses 2011; 27:669–680.
7. McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF. The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol 2010; 10:11–23.
8. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 2004; 200:749–759.
9. Blankson JN, Finzi D, Pierson TC, Sabundayo BP, Chadwick K, Margolick JB, et al. Biphasic decay of latently infected CD4+ T cells in acute human immunodeficiency virus type 1 infection. J Infect Dis 2000; 182:1636–1642.
10. Levy JA. HIV pathogenesis: 25 years of progress and persistent challenges. AIDS 2009; 23:147–160.
11. Haase AT. Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu Rev Med 2011; 62:127–139.
12. Loffredo JT, Friedrich TC, Leon EJ, Stephany JJ, Rodrigues DS, Spencer SP, et al. CD8+ T cells from SIV elite controller macaques recognize Mamu-B*08-bound epitopes and select for widespread viral variation. PLoS One 2007; 2:e1152.
13. Deeks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 2007; 27:406–416.
14. Munoz A, Kirby AJ, He YD, Margolick JB, Visscher BR, Rinaldo CR, et al. Long-term survivors with HIV-1 infection: incubation period and longitudinal patterns of CD4+ lymphocytes. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8:496–505.
15. Alexander L, Weiskopf E, Greenough TC, Gaddis NC, Auerbach MR, Malim MH, et al. Unusual polymorphisms in human immunodeficiency virus type 1 associated with nonprogressive infection. J Virol 2000; 74:4361–4376.
16. Miura T, Brockman MA, Brumme CJ, Brumme ZL, Carlson JM, Pereyra F, et al. Genetic characterization of human immunodeficiency virus type 1 in elite controllers: lack of gross genetic defects or common amino acid changes. J Virol 2008; 82:8422–8430.
17. Blankson JN, Bailey JR, Thayil S, Yang HC, Lassen K, Lai J, et al. Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors. J Virol 2007; 81:2508–2518.
18. Mens H, Kearney M, Wiegand A, Shao W, Schonning K, Gerstoft J, et al. HIV-1 continues to replicate and evolve in patients with natural control of HIV infection. J Virol 2010; 84:12971–12981.
19. O’Connell KA, Hegarty RW, Siliciano RF, Blankson JN. Viral suppression of multiple escape mutants by de novo CD8(+) T cell responses in a human immunodeficiency virus-1 infected elite suppressor. Retrovirology 2011; 8:63.
20. Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. Immunity 2011; 35:161–168.
21. Gerlach C, van Heijst JW, Swart E, Sie D, Armstrong N, Kerkhoven RM, et al. One naive T cell, multiple fates in CD8+ T cell differentiation. J Exp Med 2010; 207:1235–1246.
22. Kaech SM, Ahmed R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat Immunol 2001; 2:415–422.
23. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999; 401:708–712.
24. Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, Antia R, et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 2003; 4:225–234.
25. Hanke T. Vehicles for genetic vaccines against human immunodeficiency virus: induction of T cell-mediated immune responses. Curr Mol Med 2001; 1:123–135.
26. Moss B. Use of vaccinia virus vectors for development of AIDS vaccines. AIDS 1988; 2 (Suppl 1):S103–S105.
27. Robinson HL, Amara RR. T cell vaccines for microbial infections. Nat Med 2005; 11:S25–S32.
28. Welsh RM, Selin LK, Szomolanyi-Tsuda E. Immunological memory to viral infections. Annu Rev Immunol 2004; 22:711–743.
29. Li Q, Skinner PJ, Ha SJ, Duan L, Mattila TL, Hage A, et al. Visualizing antigen-specific and infected cells in situ predicts outcomes in early viral infection. Science 2009; 323:1726–1729.
30. Stock AT, Jones CM, Heath WR, Carbone FR. Cutting edge: central memory T cells do not show accelerated proliferation or tissue infiltration in response to localized herpes simplex virus-1 infection. J Immunol 2006; 177:1411–1415.
31. Ahlers JD, Belyakov IM. Memories that last forever: strategies for optimizing vaccine T-cell memory. Blood 2010; 115:1678–1689.
32. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 1994; 68:6103–6110.
33. Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994; 68:4650–4655.
34. 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.
35. Reimann KA, Tenner-Racz K, Racz P, Montefiori DC, Yasutomi Y, Lin W, et al. Immunopathogenic events in acute infection of rhesus monkeys with simian immunodeficiency virus of macaques. J Virol 1994; 68:2362–2370.
36. Matano T, Shibata R, Siemon C, Connors M, Lane HC, Martin MA. Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol 1998; 72:164–169.
37. Connor RI, Montefiori DC, Binley JM, Moore JP, Bonhoeffer S, Gettie A, et al. Temporal analyses of virus replication, immune responses, and efficacy in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine. J Virol 1998; 72:7501–7509.
38. Schmitz JE. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999; 283:857–860.
39. Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J, et al. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 1999; 189:991–998.
40. Hay CM, Ruhl DJ, Basgoz NO, Wilson CC, Billingsley JM, DePasquale MP, et al. Lack of viral escape and defective in vivo activation of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes in rapidly progressive infection. J Virol 1999; 73:5509–5519.
41. Draenert R, Verrill CL, Tang Y, Allen TM, Wurcel AG, Boczanowski M, et al. Persistent recognition of autologous virus by high-avidity CD8 T cells in chronic, progressive human immunodeficiency virus type 1 infection. J Virol 2004; 78:630–641.
42. Walker CM, Moody DJ, Stites DP, Levy JA. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 1986; 234:1563–1566.
43. Pantaleo G, Demarest JF, Soudeyns H, Graziosi C, Denis F, Adelsberger JW, et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 1994; 370:463–467.
44. Chakrabarti L, Guyader M, Alizon M, Daniel MD, Desrosiers RC, Tiollais P, et al. Sequence of simian immunodeficiency virus from macaque and its relationship to other human and simian retroviruses. Nature 1987; 328:543–547.
45. Hu SL. Nonhuman primate models for AIDS vaccine research. Curr Drug Targets Infect Disord 2005; 5:193–201.
46. Valentine LE, Watkins DI. Relevance of studying T cell responses in SIV-infected rhesus macaques. Trends Microbiol 2008; 16:605–611.
47. Picker LJ. Immunopathogenesis of acute AIDS virus infection. Curr Opin Immunol 2006; 18:399–405.
48. Reynolds MR, Weiler AM, Weisgrau KL, Piaskowski SM, Furlott JR, Weinfurter JT, et al. Macaques vaccinated with live-attenuated SIV control replication of heterologous virus. J Exp Med 2008; 205:2537–2550.
49. Friedrich TC, Valentine LE, Yant LJ, Rakasz EG, Piaskowski SM, Furlott JR, et al. Subdominant CD8+ T-cell responses are involved in durable control of AIDS virus replication. J Virol 2007; 81:3465–3476.
50. Check E. AIDS vaccines: back to ’plan A’. Nature 2003; 423:912–914.
51. Keele BF, Li H, Learn GH, Hraber P, Giorgi EE, Grayson T, et al. Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1. J Exp Med 2009; 206:1117–1134.
52. 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.
53. Nixon DF, Townsend AR, Elvin JG, Rizza CR, Gallwey J, McMichael AJ. HIV-1 gag-specific cytotoxic T lymphocytes defined with recombinant vaccinia virus and synthetic peptides. Nature 1988; 336:484–487.
54. Price DA, Goulder PJ, 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.
55. Furtado MR, Balachandran R, Gupta P, Wolinsky SM. Analysis of alternatively spliced human immunodeficiency virus type-1 mRNA species, one of which encodes a novel tat-env fusion protein. Virology 1991; 185:258–270.
56. Borrow P, Lewicki H, Wei X, Horwitz MS, Peffer N, Meyers H, et al. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med 1997; 3:205–211.
57. Allen TM, O’Connor DH, Jing P, Dzuris JL, Mothe BR, Vogel TU, et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 2000; 407:386–390.
58. Chen ZW, Craiu A, Shen L, Kuroda MJ, Iroku UC, Watkins DI, et al. Simian immunodeficiency virus evades a dominant epitope-specific cytotoxic T lymphocyte response through a mutation resulting in the accelerated dissociation of viral peptide and MHC class I. J Immunol 2000; 164:6474–6479.
59. Allen TM, Yu XG, Kalife ET, Reyor LL, Lichterfeld M, John M, et al. De novo generation of escape variant-specific CD8+ T-cell responses following cytotoxic T-lymphocyte escape in chronic human immunodeficiency virus type 1 infection. J Virol 2005; 79:12952–12960.
60. Goonetilleke N, Liu MK, Salazar-Gonzalez JF, Ferrari G, Giorgi E, Ganusov VV, et al. The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J Exp Med 2009; 206:1253–1272.
61. O’Connor DH, Allen TM, Vogel TU, Jing P, DeSouza IP, Dodds E, et al. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat Med 2002; 8:493–499.
62. O’Connor D, Friedrich T, Hughes A, Allen TM, Watkins D. Understanding cytotoxic T-lymphocyte escape during simian immunodeficiency virus infection. Immunol Rev 2001; 183:115–126.
63. O’Connor DH, McDermott AB, Krebs KC, Dodds EJ, Miller JE, Gonzalez EJ, et al. A dominant role for CD8+-T-lymphocyte selection in simian immunodeficiency virus sequence variation. J Virol 2004; 78:14012–14022.
64. Bernardin F, Kong D, Peddada L, Baxter-Lowe LA, Delwart E. Human immunodeficiency virus mutations during the first month of infection are preferentially found in known cytotoxic T-lymphocyte epitopes. J Virol 2005; 79:11523–11528.
65. Goepfert PA, Lumm W, Farmer P, Matthews P, Prendergast A, Carlson JM, et al. Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients. J Exp Med 2008; 205:1009–1017.
66. Friedrich TC, Dodds EJ, Yant LJ, Vojnov L, Rudersdorf R, Cullen C, et al. Reversion of CTL escape-variant immunodeficiency viruses in vivo. Nat Med 2004; 10:275–281.
67. Leslie AJ, Pfafferott KJ, Chetty P, Draenert R, Addo MM, Feeney M, et al. HIV evolution: CTL escape mutation and reversion after transmission. Nat Med 2004; 10:282–289.
68. Crawford H, Prado JG, Leslie A, Hue S, Honeyborne I, Reddy S, et al. Compensatory mutation partially restores fitness and delays reversion of escape mutation within the immunodominant HLA-B*5703-restricted Gag epitope in chronic human immunodeficiency virus type 1 infection. J Virol 2007; 81:8346–8351.
69. Kelleher AD, Long C, Holmes EC, Allen RL, Wilson J, Conlon C, et al. Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses. J Exp Med 2001; 193:375–386.
70. Schneidewind A, Brockman MA, Yang R, Adam RI, Li B, Le Gall S, et al. Escape from the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication. J Virol 2007; 81:12382–12393.
71. Brockman MA, Schneidewind A, Lahaie M, Schmidt A, Miura T, Desouza I, et al. Escape and compensation from early HLA-B57-mediated cytotoxic T-lymphocyte pressure on human immunodeficiency virus type 1 Gag alter capsid interactions with cyclophilin A. J Virol 2007; 81:12608–12618.
72. Martinez-Picado J, Prado JG, Fry EE, Pfafferott K, Leslie A, Chetty S, et al. Fitness cost of escape mutations in p24 Gag in association with control of human immunodeficiency virus type 1. J Virol 2006; 80:3617–3623.
73. Streeck H, Jolin JS, Qi Y, Yassine-Diab B, Johnson RC, Kwon DS, et al. Human immunodeficiency virus type 1-specific CD8+ T-cell responses during primary infection are major determinants of the viral set point and loss of CD4+ T cells. J Virol 2009; 83:7641–7648.
74. Vanderford TH, Bleckwehl C, Engram JC, Dunham RM, Klatt NR, Feinberg MB, et al. Viral CTL escape mutants are generated in lymph nodes and subsequently become fixed in plasma and rectal mucosa during acute SIV infection of macaques. PLoS Pathog 2011; 7:e1002048.
75. Dong T, Zhang Y, Xu KY, Yan H, James I, Peng Y, et al. Extensive HLA-driven viral diversity following a narrow-source HIV-1 outbreak in rural China. Blood 2011; 118:98–106.
76. Wood N, Bhattacharya T, Keele BF, Giorgi E, Liu M, Gaschen B, et al. HIV evolution in early infection: selection pressures, patterns of insertion and deletion, and the impact of APOBEC. PLoS Pathog 2009; 5:e1000414.
77. Li B, Gladden AD, Altfeld M, Kaldor JM, Cooper DA, Kelleher AD, et al. Rapid reversion of sequence polymorphisms dominates early human immunodeficiency virus type 1 evolution. J Virol 2007; 81:193–201.
78. Brumme ZL, Tao I, Szeto S, Brumme CJ, Carlson JM, Chan D, et al. Human leukocyte antigen-specific polymorphisms in HIV-1 Gag and their association with viral load in chronic untreated infection. AIDS 2008; 22:1277–1286.
79. Wang YE, Li B, Carlson JM, Streeck H, Gladden AD, Goodman R, et al. Protective HLA class I alleles that restrict acute-phase CD8+ T-cell responses are associated with viral escape mutations located in highly conserved regions of human immunodeficiency virus type 1. J Virol 2009; 83:1845–1855.
80. Altfeld M, Kalife ET, Qi Y, Streeck H, Lichterfeld M, Johnston MN, et al. HLA alleles associated with delayed progression to AIDS contribute strongly to the initial CD8(+) T cell response against HIV-1. PLoS Med 2006; 3:e403.
81. Ganusov VV, Goonetilleke N, Liu MK, Ferrari G, Shaw GM, McMichael AJ, et al. Fitness costs and diversity of the cytotoxic T lymphocyte (CTL) response determine the rate of CTL escape during acute and chronic phases of HIV infection. J Virol 2011; 85:10518–10528.
82. Brumme ZL, Li C, Miura T, Sela J, Rosato PC, Brumme CJ, et al. Reduced replication capacity of NL4-3 recombinant viruses encoding reverse transcriptase-integrase sequences from HIV-1 elite controllers. J Acquir Immune Defic Syndr 2011; 56:100–108.
83. Appay V, Douek DC, Price DA. CD8+ T cell efficacy in vaccination and disease. Nat Med 2008; 14:623–628.
84. 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.
85. Kaslow RA, Carrington M, Apple R, Park L, Munoz A, Saah AJ, et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 1996; 2:405–411.
86. Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ, et al. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 1999; 283:1748–1752.
87. Migueles SA, Sabbaghian MS, Shupert WL, Bettinotti MP, Marincola FM, Martino L, et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci U S A 2000; 97:2709–2714.
88. Yant LJ, Friedrich TC, Johnson RC, May GE, Maness NJ, Enz AM, et al. The high-frequency major histocompatibility complex class I allele Mamu-B*17 is associated with control of simian immunodeficiency virus SIVmac239 replication. J Virol 2006; 80:5074–5077.
89. Loffredo JT, Maxwell J, Qi Y, Glidden CE, Borchardt GJ, Soma T, et al. Mamu-B*08-positive macaques control simian immunodeficiency virus replication. J Virol 2007; 81:8827–8832.
90. Kiepiela P, Leslie AJ, Honeyborne I, Ramduth D, Thobakgale C, Chetty S, et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 2004; 432:769–775.
91. Zhang ZQ, Fu TM, Casimiro DR, Davies ME, Liang X, Schleif WA, et al. Mamu-A*01 allele-mediated attenuation of disease progression in simian-human immunodeficiency virus infection. J Virol 2002; 76:12845–12854.
92. Fadda L, O’Connor GM, Kumar S, Piechocka-Trocha A, Gardiner CM, Carrington M, et al. Common HIV-1 peptide variants mediate differential binding of KIR3DL1 to HLA-Bw4 molecules. J Virol 2011; 85:5970–5974.
93. Brackenridge S, Evans EJ, Toebes M, Goonetilleke N, Liu MK, di Gleria K, et al. An early HIV mutation within an HLA-B*57-restricted T cell epitope abrogates binding to the killer inhibitory receptor 3DL1. J Virol 2011; 85:5415–5422.
94. Ploquin MJ-Y, Jacquelin B, Jochems SP, Barré-Sinoussi F, Müller-Trutwin MC. Innate immunity in the control of HIV/AIDS: recent advances and open questions. AIDS 2012; 26:1269–1279.
95. Goulder PJ, Phillips RE, Colbert RA, McAdam S, Ogg G, Nowak MA, et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med 1997; 3:212–217.
96. Ammaranond P, Zaunders J, Satchell C, van Bockel D, Cooper DA, Kelleher AD. A new variant cytotoxic T lymphocyte escape mutation in HLA-B27-positive individuals infected with HIV type 1. AIDS Res Hum Retroviruses 2005; 21:395–397.
97. Feeney ME, Tang Y, Roosevelt KA, Leslie AJ, McIntosh K, Karthas N, et al. Immune escape precedes breakthrough human immunodeficiency virus type 1 viremia and broadening of the cytotoxic T-lymphocyte response in an HLA-B27-positive long-term-nonprogressing child. J Virol 2004; 78:8927–8930.
98. Betts MR, Exley B, Price DA, Bansal A, Camacho ZT, Teaberry V, et al. Characterization of functional and phenotypic changes in anti-Gag vaccine-induced T cell responses and their role in protection after HIV-1 infection. Proc Natl Acad Sci U S A 2005; 102:4512–4517.
99. Weinfurter JT, May GE, Soma T, Hessell AJ, Leon EJ, Macnair CE, et al. Macaque long-term nonprogressors resist superinfection with multiple CD8+ T cell escape variants of simian immunodeficiency virus. J Virol 2011; 85:530–541.
100. Miura T, Brockman MA, Schneidewind A, Lobritz M, Pereyra F, Rathod A, et al. HLA-B57/B*5801 human immunodeficiency virus type 1 elite controllers select for rare gag variants associated with reduced viral replication capacity and strong cytotoxic T-lymphocyte [corrected] recognition. J Virol 2009; 83:2743–2755.
101. McDermott AB, O’Connor DH, Fuenger S, Piaskowski S, Martin S, Loffredo J, et al. Cytotoxic T-lymphocyte escape does not always explain the transient control of simian immunodeficiency virus SIVmac239 viremia in adenovirus-boosted and DNA-primed Mamu-A*01-positive rhesus macaques. J Virol 2005; 79:15556–15566.
102. Maness NJ, Yant LJ, Chung C, Loffredo JT, Friedrich TC, Piaskowski SM, et al. Comprehensive immunological evaluation reveals surprisingly few differences between elite controller and progressor Mamu-B*17-positive Simian immunodeficiency virus-infected rhesus macaques. J Virol 2008; 82:5245–5254.
103. Bailey JR, Williams TM, Siliciano RF, Blankson JN. Maintenance of viral suppression in HIV-1-infected HLA-B*57+ elite suppressors despite CTL escape mutations. J Exp Med 2006; 203:1357–1369.
104. Barouch DH, Kunstman J, Kuroda MJ, Schmitz JE, Santra S, Peyerl FW, et al. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 2002; 415:335–339.
105. Vojnov L, Martins MA, Almeida JR, Ende Z, Rakasz EG, Reynolds MR, et al. GagCM9-specific CD8+ T cells expressing limited public TCR clonotypes do not suppress SIV replication in vivo. PLoS One 2011; 6:e23515.
106. Price DA, Asher TE, Wilson NA, Nason MC, Brenchley JM, Metzler IS, et al. Public clonotype usage identifies protective Gag-specific CD8+ T cell responses in SIV infection. J Exp Med 2009; 206:923–936.
107. Iglesias MC, Almeida JR, Fastenackels S, van Bockel DJ, Hashimoto M, Venturi V, et al. Escape from highly effective public CD8+ T-cell clonotypes by HIV. Blood 2011; 118:2138–2149.
108. 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.
109. Miles JJ, Douek DC, Price DA. Bias in the alphabeta T-cell repertoire: implications for disease pathogenesis and vaccination. Immunol Cell Biol 2011; 89:375–387.
110. Allen TM, Jing P, Calore B, Horton H, O’Connor DH, Hanke T, et al. Effects of cytotoxic T lymphocytes (CTL) directed against a single simian immunodeficiency virus (SIV) Gag CTL epitope on the course of SIVmac239 infection. J Virol 2002; 76:10507–10511.
111. 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.
112. Zimmerli SC, Harari A, Cellerai C, Vallelian F, Bart PA, Pantaleo G. HIV-1-specific IFN-gamma/IL-2-secreting CD8 T cells support CD4-independent proliferation of HIV-1-specific CD8 T cells. Proc Natl Acad Sci U S A 2005; 102:7239–7244.
113. Arrode G, Finke JS, Zebroski H, Siegal FP, Steinman RM. CD8+ T cells from most HIV-1-infected patients, even when challenged with mature dendritic cells, lack functional recall memory to HIV gag but not other viruses. Eur J Immunol 2005; 35:159–170.
114. Horton H, Frank I, Baydo R, Jalbert E, Penn J, Wilson S, et al. Preservation of T cell proliferation restricted by protective HLA alleles is critical for immune control of HIV-1 infection. J Immunol 2006; 177:7406–7415.
115. Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, Hallahan CW, et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 2002; 3:1061–1068.
116. Hersperger AR, Pereyra F, Nason M, Demers K, Sheth P, Shin LY, et al. Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control. PLoS Pathog 2010; 6:e1000917.
117. Williams LD, Bansal A, Sabbaj S, Heath SL, Song W, Tang J, et al. Interleukin-21-producing HIV-1-specific CD8 T cells are preferentially seen in elite controllers. J Virol 2011; 85:2316–2324.
118. Saez-Cirion A, Lacabaratz C, Lambotte O, Versmisse P, Urrutia A, Boufassa F, et al. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci U S A 2007; 104:6776–6781.
119. Migueles SA, Osborne CM, Royce C, Compton AA, Joshi RP, Weeks KA, et al. Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity 2008; 29:1009–1021.
120. Elahi S, Dinges WL, Lejarcegui N, Laing KJ, Collier AC, Koelle DM, et al. Protective HIV-specific CD8+ T cells evade Treg cell suppression. Nat Med 2011; 17:989–995.
121. Weiss L, Piketty C, Assoumou L, Didier C, Caccavelli L, Donkova-Petrini V, et al. Relationship between regulatory T cells and immune activation in human immunodeficiency virus-infected patients interrupting antiretroviral therapy. PLoS One 2010; 5:e11659.
122. Hunt PW, Landay AL, Sinclair E, Martinson JA, Hatano H, Emu B, et al. A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers. PLoS One 2011; 6:e15924.
123. Weiss L, Letimier FA, Carriere M, Maiella S, Donkova-Petrini V, Targat B, et al. In vivo expansion of naive and activated CD4+CD25+FOXP3+ regulatory T cell populations in interleukin-2-treated HIV patients. Proc Natl Acad Sci U S A 2010; 107:10632–10637.
124. Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 2006; 203:2281–2292.
125. Petrovas C, Chaon B, Ambrozak DR, Price DA, Melenhorst JJ, Hill BJ, et al. Differential association of programmed death-1 and CD57 with ex vivo survival of CD8+ T cells in HIV infection. J Immunol 2009; 183:1120–1132.
126. Zhang JY, Zhang Z, Wang X, Fu JL, Yao J, Jiao Y, et al. PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors. Blood 2007; 109:4671–4678.
127. 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.
128. Streeck H, Brumme ZL, Anastario M, Cohen KW, Jolin JS, Meier A, et al. Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8+ T cells. PLoS Med 2008; 5:e100.
129. Mudd PA, Watkins DI. Understanding animal models of elite control: windows on effective immune responses against immunodeficiency viruses. Curr Opin HIV AIDS 2011; 6:197–201.
130. Porichis F, Kaufmann DE. HIV-specific CD4 T cells and immune control of viral replication. Curr Opin HIV AIDS 2011; 6:174–180.
131. Autran B, Descours B, Avettand-Fenoel V, Rouzioux C. Elite controllers as a model of functional cure. Curr Opin HIV AIDS 2011; 6:181–187.
132. Saunders KO, Rudicell RS, Nabel GJ. The design and evaluation of HIV-1 vaccines. AIDS 2012; 26:1293–1302.
133. Saez-Cirion A, Sinet M, Shin SY, Urrutia A, Versmisse P, Lacabaratz C, et al. Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses. J Immunol 2009; 182:7828–7837.
134. Sacha JB, Chung C, Rakasz EG, Spencer SP, Jonas AK, Bean AT, et al. Gag-specific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and viral protein expression. J Immunol 2007; 178:2746–2754.
135. 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.
136. Liang X, Casimiro DR, Schleif WA, Wang F, Davies ME, Zhang ZQ, et al. Vectored Gag and Env but not Tat show efficacy against simian-human immunodeficiency virus 89.6P challenge in Mamu-A*01-negative rhesus monkeys. J Virol 2005; 79:12321–12331.
137. Kawada M, Tsukamoto T, Yamamoto H, Iwamoto N, Kurihara K, Takeda A, et al. Gag-specific cytotoxic T-lymphocyte-based control of primary simian immunodeficiency virus replication in a vaccine trial. J Virol 2008; 82:10199–10206.
138. Julg B, Williams KL, Reddy S, Bishop K, Qi Y, Carrington M, et al. Enhanced anti-HIV functional activity associated with Gag-specific CD8 T-cell responses. J Virol 2010; 84:5540–5549.
139. Riviere Y, McChesney MB, Porrot F, Tanneau-Salvadori F, Sansonetti P, Lopez O, et al. Gag-specific cytotoxic responses to HIV type 1 are associated with a decreased risk of progression to AIDS-related complex or AIDS. AIDS Res Hum Retroviruses 1995; 11:903–907.
140. Masemola A, Mashishi T, Khoury G, Mohube P, Mokgotho P, Vardas E, et al. Hierarchical targeting of subtype C human immunodeficiency virus type 1 proteins by CD8+ T cells: correlation with viral load. J Virol 2004; 78:3233–3243.
141. Nqoko B, Day CL, Mansoor N, De Kock M, Hughes EJ, Hawkridge T, et al. HIV-specific gag responses in early infancy correlate with clinical outcome and inversely with viral load. AIDS Res Hum Retroviruses 2011; 27:1311–1316.
142. Allen TM, Mortara L, Mothe BR, Liebl M, Jing P, Calore B, et al. Tat-vaccinated macaques do not control simian immunodeficiency virus SIVmac239 replication. J Virol 2002; 76:4108–4112.
143. Yang OO, Sarkis PT, Ali A, Harlow JD, Brander C, Kalams SA, et al. Determinant of HIV-1 mutational escape from cytotoxic T lymphocytes. J Exp Med 2003; 197:1365–1375.
144. van Baalen CA, Guillon C, van Baalen M, Verschuren EJ, Boers PH, Osterhaus AD, et al. Impact of antigen expression kinetics on the effectiveness of HIV-specific cytotoxic T lymphocytes. Eur J Immunol 2002; 32:2644–2652.
145. Briggs JA, Simon MN, Gross I, Krausslich HG, Fuller SD, Vogt VM, et al. The stoichiometry of Gag protein in HIV-1. Nat Struct Mol Biol 2004; 11:672–675.
146. Sacha JB, Chung C, Reed J, Jonas AK, Bean AT, Spencer SP, et al. Pol-specific CD8+ T cells recognize simian immunodeficiency virus-infected cells prior to Nef-mediated major histocompatibility complex class I downregulation. J Virol 2007; 81:11703–11712.
147. Lobritz MA, Marozsan AJ, Troyer RM, Arts EJ. Natural variation in the V3 crown of human immunodeficiency virus type 1 affects replicative fitness and entry inhibitor sensitivity. J Virol 2007; 81:8258–8269.
148. Quinones-Mateu ME, Ball SC, Marozsan AJ, Torre VS, Albright JL, Vanham G, et al. A dual infection/competition assay shows a correlation between ex vivo human immunodeficiency virus type 1 fitness and disease progression. J Virol 2000; 74:9222–9233.
149. Troyer RM, McNevin J, Liu Y, Zhang SC, Krizan RW, Abraha A, et al. Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response. PLoS Pathog 2009; 5:e1000365.
150. Rolland M, Nickle DC, Mullins JI. HIV-1 group M conserved elements vaccine. PLoS Pathog 2007; 3:e157.
151. Kong WP, Wu L, Wallstrom TC, Fischer W, Yang ZY, Ko SY, et al. Expanded breadth of the T-cell response to mosaic human immunodeficiency virus type 1 envelope DNA vaccination. J Virol 2009; 83:2201–2215.
152. Santra S, Liao HX, Zhang R, Muldoon M, Watson S, Fischer W, et al. Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys. Nat Med 2010; 16:324–328.
153. Barouch DH, O’Brien KL, Simmons NL, King SL, Abbink P, Maxfield LF, et al. Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat Med 2010; 16:319–323.
154. Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the STEP Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 2008; 372:1881–1893.
155. See http://
156. McElrath MJ, De Rosa SC, Moodie Z, Dubey S, Kierstead L, Janes H, et al. HIV-1 vaccine-induced immunity in the test-of-concept STEP Study: a case–cohort analysis. Lancet 2008; 372:1894–1905.
157. Li F, Finnefrock AC, Dubey SA, Korber BT, Szinger J, Cole S, et al. Mapping HIV-1 vaccine induced T-cell responses: bias towards less-conserved regions and potential impact on vaccine efficacy in the STEP study. PLoS One 2011; 6:e20479.
158. Frahm N, DeCamp AC, Friedrich DP, Carter DK, Defawe OD, Kublin JG, et al. Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine. J Clin Invest 2012; 122:359–367.
159. West EE, Youngblood B, Tan WG, Jin HT, Araki K, Alexe G, et al. Tight regulation of memory CD8(+) T cells limits their effectiveness during sustained high viral load. Immunity 2011; 35:285–298.
160. Fitzgerald DW, Janes H, Robertson M, Coombs R, Frank I, Gilbert P, et al. An Ad5-vectored HIV-1 vaccine elicits cell-mediated immunity but does not affect disease progression in HIV-1-infected male subjects: results from a randomized placebo-controlled trial (the STEP study). J Infect Dis 2011; 203:765–772.
161. Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien JP, et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 2011; 477:466–470.
162. Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 2010; 329:811–817.
163. Kim JH, Rerks-Ngarm S, Excler JL, Michael NL. HIV vaccines: lessons learned and the way forward. Curr Opin HIV AIDS 2010; 5:428–434.
164. Hansen SG, Vieville C, Whizin N, Coyne-Johnson L, Siess DC, Drummond DD, et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat Med 2009; 15:293–299.
165. Hansen SG, Ford JC, Lewis MS, Ventura AB, Hughes CM, Coyne-Johnson L, et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 2011; 473:523–527.
166. Woodland DL. Jump-starting the immune system: prime-boosting comes of age. Trends Immunol 2004; 25:98–104.
167. Horton H, Vogel TU, Carter DK, Vielhuber K, Fuller DH, Shipley T, et al. Immunization of rhesus macaques with a DNA prime/modified vaccinia virus Ankara boost regimen induces broad simian immunodeficiency virus (SIV)-specific T-cell responses and reduces initial viral replication but does not prevent disease progression following challenge with pathogenic SIVmac239. J Virol 2002; 76:7187–7202.
168. Smith JM, Amara RR, Campbell D, Xu Y, Patel M, Sharma S, et al. DNA/MVA vaccine for HIV type 1: effects of codon-optimization and the expression of aggregates or virus-like particles on the immunogenicity of the DNA prime. AIDS Res Hum Retroviruses 2004; 20:1335–1347.
169. Amara RR, Villinger F, Altman JD, Lydy SL, O’Neil SP, Staprans SI, et al. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 2001; 292:69–74.
170. Casimiro DR, Cox K, Tang A, Sykes KJ, Feng M, Wang F, et al. Efficacy of multivalent adenovirus-based vaccine against simian immunodeficiency virus challenge. J Virol 2010; 84:2996–3003.
171. Casimiro DR, Wang F, Schleif WA, Liang X, Zhang ZQ, Tobery TW, et al. Attenuation of simian immunodeficiency virus SIVmac239 infection by prophylactic immunization with DNA and recombinant adenoviral vaccine vectors expressing Gag. J Virol 2005; 79:15547–15555.
172. Wilson NA, Reed J, Napoe GS, Piaskowski S, Szymanski A, Furlott J, et al. Vaccine-induced cellular immune responses reduce plasma viral concentrations after repeated low-dose challenge with pathogenic simian immunodeficiency virus SIVmac239. J Virol 2006; 80:5875–5885.
173. Wilson NA, Keele BF, Reed JS, Piaskowski SM, MacNair CE, Bett AJ, et al. Vaccine-induced cellular responses control simian immunodeficiency virus replication after heterologous challenge. J Virol 2009; 83:6508–6521.
174. Liu J, Keele BF, Li H, Keating S, Norris PJ, Carville A, et al. Low-dose mucosal simian immunodeficiency virus infection restricts early replication kinetics and transmitted virus variants in rhesus monkeys. J Virol 2010; 84:10406–10412.
175. Hudgens MG, Gilbert PB, Mascola JR, Wu CD, Barouch DH, Self SG. Power to detect the effects of HIV vaccination in repeated low-dose challenge experiments. J Infect Dis 2009; 200:609–613.
176. McDermott AB, Mitchen J, Piaskowski S, De Souza I, Yant LJ, Stephany J, et al. Repeated low-dose mucosal simian immunodeficiency virus SIVmac239 challenge results in the same viral and immunological kinetics as high-dose challenge: a model for the evaluation of vaccine efficacy in nonhuman primates. J Virol 2004; 78:3140–3144.
177. Winstone N, Wilson AJ, Morrow G, Boggiano C, Chiuchiolo MJ, Lopez M, et al. Enhanced control of pathogenic Simian immunodeficiency virus SIVmac239 replication in macaques immunized with an interleukin-12 plasmid and a DNA prime-viral vector boost vaccine regimen. J Virol 2011; 85:9578–9587.
178. Liu J, O’Brien KL, Lynch DM, Simmons NL, La Porte A, Riggs AM, et al. Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys. Nature 2009; 457:87–91.
179. Barouch DH, Liu J, Li H, Maxfield LF, Abbink P, Lynch DM, et al. Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature 2012; 482:89–93.
180. Remmerswaal EB, Havenith SH, Idu MM, van Leeuwen EM, van Donselaar KA, Ten Brinke A, et al. Human virus-specific effector-type T cells accumulate in blood but not in lymph nodes. Blood 2012; 119:1702–1712.
181. Picker LJ, Hansen SG, Lifson JD. New paradigms for HIV/AIDS vaccine development. Annu Rev Med 2012; 63:95–111.
182. Hansen SG, Powers CJ, Richards R, Ventura AB, Ford JC, Siess D, et al. Evasion of CD8+ T cells is critical for superinfection by cytomegalovirus. Science 2010; 328:102–106.

CD8+ T cell; HIV disease; HIV infection; HIV vaccine

© 2012 Lippincott Williams & Wilkins, Inc.