Definition
T-cells play a central role in both the control and pathogenesis of HIV infection. While T-cell responses against HIV-1 infection have been studied in great detail, much less is known about T-cells in the context of HIV-2. This entry summarizes current understanding of the quantitative and qualitative characteristics of HIV-2-specific CD8+ and CD4+ T-cell responses, highlighting key areas in which they may differ from responses against HIV-1, and the clinical implications of such disparities.
Introduction
Although HIV-1 and HIV-2 share substantial similarity in terms of genome and life cycle, there are clear epidemiological and prognostic distinctions between them. An important distinguishing feature of infection is the distribution and time to clinical progression (Marlink et al. 1994). In contrast to HIV-1 infection, where the overwhelming majority of treatment-naïve patients develop AIDS within approximately a decade, the outcome of HIV-2 infection follows an unusual bimodal distribution, with more than half of untreated patients exerting strong control over the virus and the remaining patients progressing toward clinically indistinguishable end-stage disease (Brun-Vezinet et al. 1987; Clavel et al. 1987). Uniquely, the patients that do progress to AIDS maintain significantly higher CD4+ lymphocyte counts and longer survival times following symptomatic onset than HIV-1 patients at the equivalent stage (Martinez-Steele et al. 2007). Additionally, long-term nonprogressors (LTNPs) and elite controllers (ECs) are significantly overrepresented in HIV-2 infection, with rates as high as 37 % in some cohorts (Thiebaut et al. 2011; van der Loeff et al. 2010) – markedly higher than the values below 1 % typically recorded in the case of HIV-1.
The associated mortality rates of HIV-1 and HIV-2 infection are therefore vastly different. Relative to the uninfected population, HIV-1 patients present with a 10–20-fold increase in mortality, while in HIV-2 patients it is only twofold (Mulder et al. 1994; Poulsen et al. 1997; van Tienen et al. 2011). HIV-2-associated mortality risk is also significantly correlated with plasma viral load, with low levels of circulating viremia being strongly predictive of long-term survival and good clinical outcome (Ariyoshi et al. 2000; Berry et al. 2002; van der Loeff et al. 2010). It has been well established in the case of HIV-1 that the control of acute viremia and determination of the viral set point are themselves associated with efficient and timely T-cellular responses (Borrow et al. 1994; Koup et al. 1994; Ranasinghe et al. 2012). Furthermore, recent studies have since revealed that robust T-cell responses are also elicited in seropositive HIV-2 patients. From these observations there is mounting evidence for an important role of T-cells in HIV-2 control and disease progression.
Background
T-cells are important players in the context of HIV-1 infection. The roles of CD4+ and CD8+ T-cells in both viral control and pathogenesis are extensive and will be discussed in detail in other entries (HIV & SIV, CD4 T cell responses to, HIV & SIV, CD8 T cell responses to). Briefly, CD4+ lymphocytes orchestrate the immune response by activating a diverse range of innate and adaptive effector cells, while CD8+ lymphocytes lyse infected cells and secrete antiviral factors that suppress infection through noncytotoxic mechanisms.
As a result of intense and long-standing investigation, much is known about the role of T-cells in HIV-1 infection. However, it is arguably less clear for HIV-2, due largely to the relative paucity of studies into this viral infection. Furthermore, investigations that draw direct comparisons between HIV-1 and HIV-2 often fail to stratify findings based on important clinical parameters, having substantial implications for proper interpretation of the data. For example, despite the characteristically lower viral load of HIV-2 patients, they are often directly compared to HIV-1 patients as a whole, rather than more appropriate subsets such as LTNPs.
Despite these limitations, a clear picture is being developed of not only the function of T-cells in the context of HIV-2, but also how the response differs from HIV-1 infection, and the potential consequences for viral control and patient prognosis.
CD8+ Virus-Specific T-Lymphocyte Responses: HIV-1 Versus HIV-2
The earliest published evidence for a role of CD8+ virus-specific T-cell responses in the control of HIV-2 infection came from observations in the macaque model that gag-, pol-, and env-specific cytotoxic responses could be detected in the blood of animals infected with HIV-2BEN (Voss et al. 1992). However, the specific epitopes recognized by the generated lymphocytes were not identified at the time.
Soon after, the first description of HIV-2-specific T-cell responses in a human study was reported, following the observation that gag-specific cytotoxic T-lymphocytes against an identifiable epitope (1A; TPYDINQML) could be extracted from the peripheral blood mononuclear cells (PBMCs) of over 55 % of study participants in a cohort of Gambian HIV-2-infected asymptomatic patients, without the need to first restimulate the cells in vitro (Gotch et al. 1993). The study had exciting implications, in that strong HIV-2 gag-specific responses were demonstrable at a much higher prevalence than the detection in approximately 25 % of healthy HIV-1 seropositive patients the group had reported previously (Gotch et al. 1990), indicating that the increased frequency and strength of HIV-2-specific responses could be responsible for mediating enhanced control of this virus, thereby explaining its unique pathology.
However, the sample size in the study was small, limited to only nine patients, and subsequent larger studies comparing HIV-1 and HIV-2 responses failed to corroborate any substantial difference in either frequency or magnitude of response in patients matched for disease stage (Gillespie et al. 2005; Jaye et al. 2004; Zheng et al. 2004). Instead, it has been suggested that the relatively reduced viral load of HIV-2 infection may be the result of either more efficient control exerted by a response of equivalent magnitude or conversely by reduced replication of the virus itself (Jaye et al. 2004).
An in-depth study of the functionality of HIV-1-/HIV-2-specific lymphocytes has since provided further support to the hypothesis that HIV-2-specific responses of equivalent magnitude may exert more efficient control on viral replication (Duvall et al. 2008). By measuring the production of cytokines and chemokines (IFN-γ, IL-2, TNF-α, & MIP-1β), as well as degranulation (CD107a) and memory function by specific viral peptide-stimulated cells, it was determined that the degree of polyfunctionality exhibited by HIV-2-specific CD8+ T-lymphocytes is markedly higher than that of cells specific for HIV-1. Furthermore, polyfunctional HIV-2-specific lymphocytes release higher levels of IFN-γ and TNF-α than their monofunctional equivalents.
The more efficient response generated in HIV-2 patients has been linked to increased promiscuity of T-cell receptor (TCR) usage, leading to greater functional flexibility (Lopes et al. 2003). While the CD8+ cells of HIV-1 patients are known to undergo oligoclonal expansion in terms of TCR repertoire, HIV-2 patient cells were found to be much more heterogeneous. The authors inferred this to be functionally important as it suggests a greater ability to tolerate variation in recognized epitopes and, by extension, generate protection against a broader range of HIV-2 strains. This is consistent with previous observations that highly oligoclonal TCR usage by HIV-1-specific cytotoxic lymphocytes is predictive of poor clinical outcome (Pantaleo et al. 1997). However, the study was not without its limitations, as the authors considered overall TCR usage, rather than performed a direct comparison between virus-specific T-cells in HIV-1 and HIV-2 infection.
A more recent study by Leligdowicz et al. – who set out to describe the TCR usage and broader characteristics of CTLs in the control of HIV-2 infection – identified a distinct differentiation phenotype from cells associated with HIV-1 infection (Leligdowicz et al. 2010). The cells were found to be CD27+ and CD28+, characteristic of early differentiation (Appay et al. 2002). The level of CD27+CD28+ cells was positively associated with CD4 count, suggestive of overrepresentation in patients with delayed progression. Furthermore, the patients unexpectedly demonstrated oligoclonal TCR Vβ segment usage in HLA-B*3501-restricted CTLs – contrary to previous evidence (Lopes et al. 2003; Pantaleo et al. 1997) – and all CTLs specific to the study epitope (HIV-2 gag NY9) made use of Vβ17. These findings are consistent with the selective expansion of high-affinity Vβ segments by affinity maturation. Furthermore, the study demonstrated greatly enhanced secretion of IFNγ and pro-inflammatory cytokines by these cells at low peptide concentrations, indicating that they have high functional avidity.
While the protective effect of CD8+ lymphocytes is largely attributed to their role in mediating cell killing, they are also able to control infection by noncytotoxic means such as the release of soluble antiviral factors. The production of high levels of β-chemokines such as MIP-1α (CCL3), MIP-1β (CCL4), and RANTES (CCL5) by CD8+ cells plays a role in the prevention and/or control of HIV-1 and SIV infections (Ahmed et al. 2002, 1999; Cocchi et al. 2000), by inhibiting binding of the M-tropic virus to the co-receptor CCR5 on entry (Alkhatib et al. 1996; Cocchi et al. 1996). The importance of CD8+ T-cell-soluble factors in the control of HIV-2 is also becoming increasingly apparent. In 1997, it was observed that filtered cell-free culture fluid containing unknown soluble factors secreted by CD8+ lymphocytes was capable of suppressing HIV-2 replication in baboon CD4+ cells, in vitro (Blackbourn et al. 1997); but the authors concluded that MIP-1α, MIP-1β, and RANTES were not responsible in this study. More recently, β-chemokine production by CD8+ lymphocytes has been shown to be greatly elevated in human HIV-2 patients relative to in uninfected controls and correlates strongly with CD4+ lymphocyte count in these individuals (Ahmed et al. 2005).
Taken together, these findings suggest that homologous HIV-2 CD8+ T-cell responses – while neither more frequent nor higher in magnitude – may exert more efficient control over infection than the equivalent HIV-1 response. This is likely to be due to increased avidity and polyfunctionality: including direct cytotoxicity and the production of high levels of soluble antiviral factors. It is therefore conceivable that the reduced viral set point characteristic of HIV-2 infection may be the result of an enhanced CD8+ lymphocyte response.
CD8+ T-Cell Epitopes and Cross-Reactivity in HIV-1 and HIV-2 Infection
The known CD8+ and CD4+ epitopes of the HIV-1 genome have been comprehensively mapped, and the Los Alamos National Laboratory (LANL) maintains an up-to-date record of these on its website (available: http://www.hiv.lanl.gov/content/immunology/maps/maps.html; accessed June 2015). However, far fewer HIV-2 epitopes have been described to date – as summarized in Table 1.
The degree to which HIV-2-directed CD8+ responses are cross-protective against HIV-1 is not well established. An early report demonstrated substantial cross-reactivity of HIV-2 patient-derived CD8+ lymphocytes against HIV-1 (Bertoletti et al. 1998). Here, the cytotoxic lymphocytes (CTLs) of 11 HIV-2 patients were tested for their ability to recognize gag-derived from four subtypes of HIV-1. Strikingly, nine of the patients responded to at least one subtype of HIV-1, while five of these patients were able to respond to at least three subtypes. Four of the five patients demonstrating broad cross-reactivity carried HLA-B*5801: a class-I human leukocyte antigen (HLA) allele associated with slow progression in HIV-1 infection (Navis et al. 2007).
However, more recent evidence suggests that HIV-2-directed CD8+ responses may in fact be less cross-protective than those generated against HIV-1 (Jennes et al. 2008). The authors found that responses from HIV-2 patient T-cells against HIV-1 gag peptides were both weaker in magnitude and narrower in breadth than the cross-reactive responses elicited by HIV-1 patients. However, responses to homologous gag were decisively broader and stronger in HIV-2 patients than HIV-1, perhaps contributing to the greater immunological control and reduced viral load characteristic of this infection.
Surprisingly, HIV-2 patient responses to homologous nef are rare (Leligdowicz et al. 2007; Zheng et al. 2007). Nef is one of the most abundant viral proteins and one of the earliest to be expressed, making it a prime target for cellular responses in HIV-1 infection. It is also a major target for cytotoxic lymphocytes in acute SIV infection (Mothe et al. 2002). As such, it is very unexpected that an equivalent response is not detected against HIV-2 nef. Possible explanations that have been proposed for the lack of HIV-2 nef-specific responses include difficulties with epitope processing, HLA-binding, TCR recognition, and/or antigen presentation resulting from the low degree of sequence homology between HIV-1 and HIV-2 nef.
CD4+ Virus-Specific T-Lymphocyte Responses: HIV-1 Versus HIV-2
HIV-1 specific CD4+ T-lymphocytes are preferentially targeted by the virus and depleted from the host repertoire. Conversely, in the majority of HIV-2 infected individuals, the CD4+ T-lymphocyte compartment remains preferentially targeted but quantitatively preserved (Duvall et al. 2007). As such, qualitative changes in their performance are likely to have a significant impact on disease control.
The proportion of patients with detectable CD4+ T-lymphocyte responses against gag is higher in HIV-2 donors than in HIV-1 donors when subjects with equivalent CD4+ counts are compared; and HIV-2 specific CD4+ T-lymphocytes demonstrate higher proliferative capacity than those specific to HIV-1 (Duvall et al. 2006). HIV-2 gag-specific CD4+ T-lymphocytes also demonstrate higher polyfunctionality than HIV-1 gag-specific cells when the production of IFN-γ, TNF-α, MIP-1β, and IL-2 and mobilization of CD107a are considered (Duvall et al. 2008).
A characteristic feature of asymptomatic, nonprogressive HIV-2 infection in humans is the maintenance of robust CD4+ T-lymphocyte help (Zheng et al. 2004). Furthermore, macaques are less likely to develop early signs of Th dysfunction when infected with nonpathogenic HIV-2 than the more pathogenic SIVmac (Dittmer et al. 1994). In summary, the preservation and persistence of both qualitative and quantitative features of CD4+ T-lymphocyte function appear to contribute to HIV-2 nonprogression and may account for viremic control in nonprogressors.
T-Lymphocyte Responses in HIV-2: Controllers Versus Progressors
HIV-2 patients who develop AIDS progress in a manner and time frame that is clinically indistinguishable from HIV-1 non-controllers (Hansmann et al. 2005; Martinez-Steele et al. 2007). It is therefore surprising that a substantial proportion of HIV-2 patients control the infection, despite it having a demonstrated potential to kill. Understanding how disease progression is avoided in these patients may provide insight as to how to control HIV-1 infection. This key interest in distinguishing LTNPs from progressors stems from a widely held hypothesis that LTNPs have acquired natural immunity against HIV and from the idea that HIV vaccines should ideally replicate the immune responses found in such patients. Unfortunately, LTNPs are extremely rare in HIV-1 infection, and it is in this regard that the paradigm of HIV-2 infection distinguishes itself (Rowland-Jones and Whittle 2007).
In HIV-2 infection, an inverse relationship has been demonstrated between CTL responses and proviral load, with stronger cytotoxic T-lymphocyte activity detected in donors with low viral load (Ariyoshi et al. 1995; Sarr et al. 2001). Moreover, type 1 Th (Th1) responses are more prolific in donors with undetectable HIV-2 RNA versus non-controllers (Alatrakchi et al. 2006). Similar to the case for CD4+ T-lymphocytes, cytotoxic and IFN-γ responses were more likely triggered by HIV-2 gag, and patients with undetectable viremia demonstrated increased competence in mounting such responses (de Silva et al. 2013; Leligdowicz et al. 2007). More specifically, CTLs from nonprogressors were more likely to target gag, while equivalent responses were absent in the majority of progressors. Ultimately, the establishment of gag-specific CD8+ polyfunctionality shows a strong inverse relationship to HIV-2 viremia in infected subjects.
This leads to a further question that has remained relatively unanswered: what accounts for the more efficient T-cell responses that occur in HIV-2 controllers than in progressors? And furthermore, why are T-cell responses more effective against HIV-2 than HIV-1? How are high levels of antiviral T-cells maintained in controllers who have undetectable plasma viral load for prolonged periods? Studies have alluded to the enhanced infectivity of dendritic cells (Manel et al. 2010) facilitated by the additional encoding of vpx by HIV-2, which antagonizes SAMHD1 (Laguette et al. 2011). The latter may have consequences for antigen processing and presentation and the elicitation of innate immune responses such as type I IFN and TRIM5α which may be more effective against HIV-2 (Cordeil et al. 2013; Ylinen et al. 2005). Yet Duvall et al. showed the lack of permissibility of blood-derived mDCs and pDCs to HIV-2 infection in culture, which suggests the possibility of alternative protective mechanisms (Duvall et al. 2007). The increased susceptibility of the HIV-2 capsid to TRIM5α recognition could potentially lead to more efficient proteasomal processing of HIV-2 proteins and thus facilitate antigen presentation.
HIV-2-Specific T-Lymphocyte Responses in Dual Infection
A highly controversial topic regarding HIV-2-specific T-cell responses is whether or not these responses confer a protective advantage against subsequent infection with HIV-1. Furthermore, in patients dually infected by both HIV-1 and HIV-2, do these responses reduce the rate of disease progression?
Dual infection of both HIV-1 and HIV-2 is extremely uncommon in developed nations, but has been reported at a prevalence of between around 0 % and 3 % of the population in some West African countries (Hamel et al. 2007; Mansson et al. 2009). A high-profile early study of Senegalese sex workers suggested that HIV-2 infection may have conferred a protective advantage against incident HIV-1 infection in these women (Travers et al. 1995). Conversely, subsequent studies failed to repeat this finding (Greenberg 2001; Norrgren et al. 1999), and the increased level of T-cell activation in dual infection is suggestive of more aggressive disease (Koblavi-Deme et al. 2004). There is also evidence to suggest that over an extended time scale, HIV-1 may outcompete HIV-2 in dually infected individuals with low CD4 counts (Raugi et al. 2013).
However, a substantial limitation to studies of dual-infected patients – in addition to the scarcity of suitable study candidates – is that often the patients recruited are those attending sexual health clinics with symptomatic HIV or coexisting sexually transmitted infections. As such, they are perhaps more likely to present with aggressive or late-stage illness. Supporting this claim, a study of individuals who were unaware of their positive status and were recruited from tuberculosis and occupational cohorts showed that the HIV-1 plasma viral load of dual-infected patients was significantly lower than patients infected with HIV-1 alone (Andersson et al. 2000).
In a comparative longitudinal study of patients either dually or singly infected, Esbjörnsson et al. found that dually infected patients progressed to AIDS on average 36 months slower than patients infected with HIV-1 alone (Esbjornsson et al. 2012). The protective effect appeared strongest in patients first infected with HIV-2 who controlled the infection and subsequently became HIV-1 positive, suggestive of an inhibitory effect mediated by existing T-cellular responses against HIV-2 antigens (de Silva et al. 2012). The conclusion to be drawn here is that HIV-2 may provide a degree of protection against HIV-1 disease progression, rather than against infection.
The direct role of T-lymphocytes in the context of dual infection has not been extensively studied. However, a 2007 study by Zheng et al. compared the T-cellular responses of HIV-1, HIV-2, and dual-infected patients to different env, gag, and nef epitopes (Zheng et al. 2007). The study demonstrated that the magnitude and frequency of responses against HIV-1 proteins were greater than those against HIV-2 and that functional CD4+ T-cell responses could be detected in all dually infected patients. Moreover, in the dual-infected patients, the level of HIV-2 gag-specific CD4+ and CD8+ T-cell response showed a significant inverse correlation with HIV-1 plasma viral load, indicative of a protective effect.
Conclusions
While the role of the cellular immune response in the context of HIV-1 infection has been well established for some time, it is only recently that a clearer picture of HIV-2-specific T-cell responses is developing, and even now we can see only the proverbial tip of the iceberg. However, with a growing number of studies comes growing evidence that T-lymphocytes play a major role in the control of the virus.
Virus-specific CD8+ cells are detectable in HIV-2 patients, but not at significantly higher frequency or magnitude than in HIV-1 infection: targeting of gag epitopes is a prominent feature of HIV-2 controllers that is frequently absent in progressors. However, T-cellular responses of equivalent magnitude may exert more efficient control on infection through increased avidity and broader functionality: for example, through direct cytotoxicity or the release of higher levels of inflammatory cytokines and soluble antiviral factors at low antigen concentrations. It is worth noting that high frequencies of virus-specific T-cells can be found in HIV-2-infected controllers who have maintained an undetectable viral load for many years.
Polyfunctional CD4+ lymphocytes may be detected in HIV-2 patients at higher levels than in HIV-1 and demonstrate substantially improved proliferative capacity. Furthermore, there is preliminary evidence from the macaque model that suggests Th cell dysfunction may be less likely to occur in HIV-2 infection than in infection with more strongly pathogenic retrovirus types, although this has not yet been corroborated in humans. The reason for the relative preservation of Th function in HIV-2 infection is not known, as HIV-2 shows the same preferential targeting of virus-specific Th cells as does HIV-1.
Collectively, these findings strongly suggest that efficient T-cellular responses may play at least a supporting role in explaining some of the significant prognostic differences between HIV-1 and HIV-2 infection. This hypothesis is supported by observations in dually infected individuals, which indicate that initial infection with HIV-2 may confer some degree of protection against subsequent infection with HIV-1, due to the presence of preexisting cellular responses.
While dissimilarities arguably exist between HIV-1- and HIV-2-specific T-cellular responses in vivo, the mechanisms by which these arise are not currently well understood. Promiscuity of TCR usage and a unique differentiation phenotype have been proposed as explanations, which would allow functional flexibility and recognition of a broader range of antigens, giving rise to a response which may or may not be cross-reactive to some degree.
In summary, the cellular immune response to HIV-2 is a complex process, which appears to have an important role in controlling infection and promoting less aggressive disease progression than that seen in HIV-1 infection. The specific processes involved and the extent of the control that it exerts are currently not well established, but active research in this field is gradually filling these gaps and paving the way to the identification of potential therapeutic targets.
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Andrews, S.M., Wong, G., Rowland-Jones, S.L. (2015). The Cellular Immune Response to HIV-2 Infection. In: Hope, T., Stevenson, M., Richman, D. (eds) Encyclopedia of AIDS. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9610-6_38-1
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