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Exceedingly high viral loads and rapid loss of CD4+ T cells in all tissue compartments is a hallmark of acute HIV-1 infection, which is often accompanied by clinical symptoms, such as fever, maculopapular rash and/or lymphadenopathy. The resolution of the clinical symptoms, and the subsequent decrease of plasma viremia are associated with the emergence of HIV-1-specific CD4+ and CD8+ T cell responses. The remarkable early inhibition of viremia by CD8+ T cells appears to be precipitated by only a limited number of specific CD8+ T cell responses, and the plasma viremia is reduced to a “set point” level. Over time the breadth and magnitude of CD8+ T cell responses increase, but without a change in the control of viral replication or further reduction in the viral set point. Moreover, the early viral set point, consequent upon the first CD8+ T cell responses, is highly predictive for the later course of disease progression. Thus, HIV-1-specific CD8+ T cell responses in acute HIV-1 infection appear to be uniquely able to efficiently suppress viral replication, while CD8+ T cell responses generated in the chronic phase of the infection appear often impaired.
The temporal association between the emergence of HIV-1-specific CD8+ T cell (CTL) responses and the decrease of viral load in the acute phase of HIV-1 infection has been the first and one of the strongest arguments for CTL as a major factor for the initial control of viral replication [1–4]. Subsequent studies were able to demonstrate that CD8+ T cells can efficiently inhibit viral replication ex vivo  and escape mutations in the CTL targeted epitopes develop early during the infection . In addition, a strong association exists for the rate of disease progression and the different human leukocyte antigens (HLA) class I alleles, underpinning the hypothesis that the interaction between the T cell receptor (TCR) of the CD8+ T cells and the HLA of the antigen-presenting cell is one of the key elements in the overall control of HIV-1 replication. After the initial peak of viremia, an early viral set point develops, which has been repeatedly associated with later disease outcome [7–8]. However, the very first CD8+ T cell responses are narrowly directed against a limited number of epitopes and despite an increase of the breadth and magnitude of the CTL response in the chronic stage of the infection, no increased control of viral replication can be observed. This suggests that the first CD8+ T cell responses are unique in their ability to efficiently suppress viral replication, while CD8+ T cell responses generated later in infection are progressively impaired. However, it is important to note, that so far no study has been able to demonstrate a clear functional correlate of CD8+ T cell mediated protection neither in acute nor chronic HIV-1 infection. Thus it is hypothetical possible that the prominent correlation of CD8+ T cell responses and drop in viral load are driven by other factors such as loss in activated CD4+ T cell targets or potential other immune mediated mechanisms.
During the first weeks of infection adaptive immunity develops, giving rise to initial HIV-1-specific CD8+ T cell responses. The early CD8+ T cell response is very narrowly directed against a few epitopes and follows a clear hierarchical immunodominance pattern . In fact, with the knowledge of the HLA class I allele, the early T cell responses can be -to some degree-successfully predicted. This will have important implications for vaccine design (table 1). Interestingly, individuals that are able to mount one of the immunodominant responses in acute HIV-1 infection have on average a lower viral set point than individuals that do not target epitopes in the acute phase of the infection (figure 1) . In addition, the preservation of these early responses has been associated with a slower disease progression and preserved number of CD4+ T cells . The correlation between first CD8+ T cell responses and early viral set point is even stronger when tested against the autologous virus . In a recent study using peptides based upon autologous viral quasispecies, the first CD8+ T cells, despite very rapid virus escape, suppressed HIV-1 as viral load was declining from its peak  (figure 1). The influence of these T cell responses vanished once the virus had escaped from the targeted epitopes. Computational modeling further suggested that a single T cell response was contributing as much as 15–35% of viral decline with multiple T cell responses . Thus, the generation of immunodominant CD8+ T cell epitope responses in the acute phase of the infection appears to have an important impact on the level of the early viral set point and subsequent disease progression.
Some subjects, however, do not develop strong CD8+ T cell responses in acute HIV-1 infection and therefore most likely experience a higher viral set point . This can be partially accounted to transmitted escape mutations in the CTL targeted epitopes. Previous studies have established that for “protective” CD8+ T cell responses such as HLA-B27KK10 or HLAB57-TW10 in p24/Gag, the lack of early responses is due to transmitted mutations within these epitopes. However, transmitted escape mutations do not explain the differences in the viral set point for the majority of the subjects lacking immunodominant CTL responses in acute HIV-1 infection. A recent study suggested that this might be due to a gradual adaptation of HIV-1 to host immune pressures occurring at the population level. In a comparison of over 2,900 viral sequences of different HIV-1 clade B cohorts world-wide it was noted that HLA allele escape mutations in the HLA-restricted epitopes accumulate at the population level, dependent on the frequency of the respective HLA class I . In line with this observation, it has been suggested that individuals expressing one of the more rare HLA supertypes have a more favorable course of the disease . This has now been linked to strong CTL selection pressure on the virus, while subjects with a more common HLA allele or HLA class I allele combination do not develop strong responses during primary HIV-1 infection. Thus, the epitopes with the strongest selective pressure are already fixed in the viral sequence at the population level for individuals that have common HLA alleles, and responses to these epitopes therefore are not observed.
The question remains why early CD8+ T cell responses are so efficient in controlling viral replication, while CTL responses generated later in infection appear impaired. Here, several explanations might equally account for this phenomenon.
Due to ongoing recombination and mutations, HIV-1 permanently escapes from the recognition by CD8+ T cell responses of the host. The continuous evolution of HIV-1 represents one of the major obstacles for vaccine design and has not only contributed to the already significant viral diversity in a single HIV-1 infected individual but also accounts for the dramatic sequence diversity among circulating viral strains at the population level. However, it has been suggested that the ability of HIV-1 to escape virus-specific immunity is finite and comes at a fitness cost to the virus. This might play a unique role in the acute phase of the infection, in which the virus has not diversified as much as seen in chronic infection. This early impairment of the virus has been suggested to be one of the central mechanisms of effective neutralizing antibody responses, in which the “chase” of antibody and viral evolution has been successfully overcome. An early viral fitness defect and therefore early suppression of HIV-1 viremia might be critical for the consecutive generation of fully functional CD8+ T cell responses as important CD4+ T cell helper signals might be preserved. Thus, immediate and early immune selection pressure might be beneficial to arrest the virus in less fit stages.
Over the last years, limited attention has been paid to the impact of HIV-1-specific CD4+ T cell responses to the control of viral replication. This is surprising as both the clearance of viruses in other viral infections such as hepatitis C [15–17], EBV [18–19] or CMV [20–22] and the prognosis in various cancers [23–26] appears to be highly dependent on antigen-specific CD4+ T helper cell responses. As well in HIV-1 infection strong HIV-1-specific CD4+ T cell responses have been associated with better control of viral replication. For example the presence of robust polyfuntional CD4+ T cell responses is one important hallmark that distinguishes non-pathogenic HIV-2 infection from pathogenic HIV-1. Moreover, a vigorous CD4+ T cell response in acute HIV-1 infection has been associated with subsequent control of viral replication  and viral escape from CD4 targeted epitopes has been observed. However, whether the presence of HIV-1-specific CD4+ T cells is the consequence of low viremia or effectively contributes to viral suppression remains unclear. Interestingly, the immunogenicity data from the ‘Thai RV144 trial’ suggest that the vaccine induced both antibody responses as well as robust CD4+ T cell responses. The rationale underlying the general exclusion of CD4+ T cells from vaccine design strategies originated from previous studies showing that HIV-1 preferentially infects HIV-1-specific CD4+ T cells. A vaccine candidate boosting these responses could in theory enhance viral replication. However, although HIV-1 preferentially infects activated HIV-1-specific CD4+ cells, the great majority of HIV-1-specific CD4+ T cells remain virus-free even in the presence of high level viremia.
During primary HIV-1 infection a massive infection of both resting and activated CD4 T cells in gut-associated lymphoid tissue occurs destroying up to 60% of these cells in the early days following infection. HIV-1-specific CD4+ T cell responses emerge simultaneously or even earlier than HIV-specific CD8+ T cell responses during primary HIV-1 infection, but decrease after the first months of infection. This contraction of the CD4+ T cell response pool has been suggested to be due to the preferential infection, however, studies from other chronic viral infection suggest that CD4+ T cell responses often naturally contract after the initial burst of viremia. Moreover, similar as for CTL epitopes, escape mutations in CD4+ T cell targeted epitopes develop, especially during the early phase of the infection [29, 33]. Although studies were able to convincingly show that HIV-1 replication can be predominantly controlled by CD8+ T cells [1–5, 34–35], the effectiveness of these CD8+ T cell responses appear to be fundamentally affected by the presence or absence of CD4+ T helper cells [36–42]. Interestingly, antigen-specific CD8+ T cells can be generated in the absence of CD4+ T cell help, but the secondary expansion upon antigen reencounter is inefficient [36, 42–44]. A robust and effective CD8+ T cell response in elite controllers has been associated with the presence and preservation of HIV-1-specific CD4+ T helper cell responses [28, 45]. These cells might be also preserved through the initiation of highly active antiretroviral therapy (HAART) during primary HIV-1 infection  and thereby maximizing HIV-1-specific CD8+ T cell responses. However, so far very little is known to what extent CD4+ T cell help is critical for CD8+ T cell mediated control and which mechanisms are required. While studies suggested that IL2 signals for CD8+ T cell proliferation is important, recent studies in the lymphochoriomeningitis virus (LCMV) model suggest that IL-21-secreting CD4+ T cell responses are also critical to prevent CD8+ T cells from becoming rapidly exhausted[47–49]; a factor which certainly plays a role in HIV-1 infection. However, whether IL-21+ CD4+ T cells are also involved in the antiviral immunity in humans has not been determined thus far.
The role of other CD4+ T cell subsets and their contribution to the control of viral replication is also controversial. Th17 cells have been implicated to be proinflammatory causing immune activation, which might be in the case of HIV-1 not beneficial. Conflicting results exists for the presence of HIV-1-specific Th17 cells and their contribution to immunpathogenesis remains to be determined. Similarly, only little is known about the role, presence and specificity of HIV-1-specific Th2 or T follicular helper cell responses, which provide important helper signals for the maturation and antibody generation of B and plasma cells. The importance of this understudied area of HIV-1 research is stressed by the recent results of the immunogenicity data of the RV144 Thai trial suggesting a potential critical interplay of induced Env-specific CD4+ T cell responses and HIV-1-specific antibody responses.
CD8+ T cell responses primed in acute HIV-1 infection have a better metabolic starting position than CD8+ T cells generated under persistent viral infection with abundance of antigen. When naïve CD8+ T cells recognize their antigen they mature to effector cells, recognizing and killing the respective target cells. After clearance of an acute viral infection, this population contracts and only a minor fraction of the effector cells develop into a long-lived memory pool. However, in chronic persistent infections and under persistent levels of antigenemia CD8+ T cells become progressively exhausted. This exhaustion follows a clear hierarchical pattern (figure 2) ; first losing the ability to proliferate, secrete Interleukin-2, their cytolytic activity and finally entering a stage of full exhaustion. This metabolic loss of functional abilities is finally followed by physical deletion. The different stages of exhaustion are reflected by the upregulation of different inhibitory molecules on the cell surface such as programmed death-1 (PD1), CTLA-4, KLRG1, TIM-3 or CD160. Although these receptors are generally upregulated under repetitive antigenic stimulation, they appear to be differently regulated suggesting a distinct modulation of these inhibitory pathways . It is also important to note that although there is a general upregulation of inhibitory receptors, this might be distinctly different at the epitope levels. Studies in human and mice demonstrated that once a CTL escape mutation in the targeted epitope develops, these receptors downregulate from the cell surface at different rates [52–53]. Similarly, the functionality of the CD8+ T cells appears to improve upon escape mutations in the targeted epitope (figure 2). However, it is not known whether the inhibitory receptors indeed decrease and the functionality of the cells generally increases or whether the pool of the different clonal CD8+ T cell population appears less exhausted as the more exhausted T cells have already entered apoptosis. Thus, to be able to analyze the functionality and phenotype of the antigen-specific CD8+ T cells, it is important to simultaneously analyze the corresponding viral sequences.
One hallmark of HIV-1 infection is a chronic activation of the immune system that not only increases the number of activated CCR5+ CD4+ target cells but also directly impairs the immune system through activation-induced cell death (AICD). Although the immune system has developed several strategies to counter-act this abundant activation, AICD has been shown to be one of the strongest contributor to CD4+ T cell loss in the case of HIV-1. One specific mechanism of evasion from hyper-activation is a specific expansion of inducible FoxP3+CD25+T regulatory cells (iTregs) following acute HIV-1 infection. Interestingly, subjects with chronic progressive infection showed significantly higher levels of iTregs compared to subjects able to control viral replication . These cells have been shown to have the ability to effectively inhibit several arms of the immune system, but the mechanism by which Tregs act is currently unknown. Both, contact-mediated activity or through soluble factors such as TGFβ or Interleukin-10 (IL10) has been suggested. Indeed, increased IL10 plasma levels in chronic HIV-1 infection have been demonstrated and suggested to contribute to the general dysfunction of CD8+ T cell responses . Taken together, HIV-1-specific CD8+ T cells which are generated in the chronic phase of the infection face an immune system, which is rather prone to reduce the immune responses than to foster their activity. Thus, their ability to more efficiently decrease the level of viral replication might be impaired due to an inhibitory cellular and cytokine milieu.
Emerging studies suggest that immune responses induced during the early stages of HIV-1 infections substantially influence disease outcome. Here, differences in the functionality and co-signals through CD4+ T helper cells appear to be critical factors for the effectiveness of CD8+ T cell responses generated in acute HIV-1 infection compared to “impaired” responses in the chronic phase of the infection. Especially, the role of CD4+ T cell help for the control of viral replication has not been sufficiently assessed and might be fundamentally important for a broader understanding of the immunpathogenesis of this disease.
Funding information: HS is funded by the Bill and Melinda Gates Foundation and NIH P01 AI074415. DN is funded through NIH AI68498.
Potential Conflicts of Interest: none
Prior Presentation: none