McDermott, Adrian B.; Koup, Richard A.
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 , preventing new infections will be critical to curtailing the epidemic (, 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.
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 . 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 . 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 . 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 ; 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.
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 .
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 .
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 . 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 , 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 , (, this issue).
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 . 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.
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 . 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], (, 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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].
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 . However, HIV-specific CD8+ T cells from HIV-infected progressors generally secrete fewer cytokines and chemokines (IFNγ or CCL3) and proliferate poorly . 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.
An increase in regulatory T cells (CD4+, CD25+, FOXP3+, CD127dim) is associated with reduced proliferation of HIV-specific CD8+, HLA-DR+, CD38+ T cells  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 . 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  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].
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 (, 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 , whereas Tat, Nef or Env proteins are less abundant . Intriguingly, Sacha et al. 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 . 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 . 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 . 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 . 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 . Predictably, HIV-infected STEP vaccine recipients with HLA-B*27, HLA-B*57 and HLA-B*58 alleles had lower virus loads . 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 (, 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 , 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. 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 . As described above, CD8+ Tem cells retain the capability to rapidly proliferate, reside in peripheral lymphoid and mucosal tissue and exert early virus control . 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 . 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 . 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 . 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.
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.
Conflicts of interest
There are no conflicts of interest.
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