CD8<sup>+</sup>T Cell Escape Mutations in Simian Immunodeficiency Virus SIVmac239 Cause Fitness Defects<i>In Vivo</i>, and Many Revert after Transmission

Mudd, Philip A.; Ericsen, Adam J.; Walsh, Andrew D.; León, Enrique J.; Wilson, Nancy A.; Maness, Nicholas J.; Friedrich, Thomas C.; Watkins, David I.

doi:10.1128/jvi.05841-11

Cited by 13 publications

(8 citation statements)

References 45 publications

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“…This observation provides strong evidence for convergent evolution in these species, both evolving a similar binding motif . It has been proposed that the preference of Mamu-B*08, and HLA-B*27, for peptides carrying Arg both at P1 and P2, may mean that the epitopes restricted by these alleles are located in protein regions of particular structural significance, that is, containing adjacent Arg residues, and as a result that are highly resistant to escape (Mudd et al, 2011). There is also similarity in the peptide-binding groove of the protective macaque allele Mamu-B*17 and HLA-B*57/58:01, HLA-A*25 and HLA-A*32, all of which have a strong preference for Trp at PC.…”

Section: Introductionmentioning

confidence: 99%

HIV and HLA Class I: An Evolving Relationship

2012

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Successful vaccine development for infectious diseases has largely been achieved in settings where natural immunity to the pathogen results in clearance in at least some individuals. HIV presents an additional challenge in that natural clearance of infection does not occur, and the correlates of immune protection are still uncertain. However, partial control of viremia and markedly different outcomes of disease are observed in HIV infected persons. Here we examine the antiviral mechanisms implicated by one variable that has been consistently associated with extremes of outcome, namely HLA class I alleles, and in particular HLA-B, and examine the mechanisms by which this modulation is likely to occur, and the impact of these interactions on evolution of the virus and the host. Studies to date provide evidence for both HLA-dependent and epitope-dependent influences on viral control and viral evolution, and have important implications for the continued quest for an effective HIV vaccine.

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Section: Introductionmentioning

confidence: 99%

HIV and HLA Class I: An Evolving Relationship

2012

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“…Of note, this "escaped" virus did not replicate as well as WT SIVmac239 in vivo, but it is not clear if this impaired replicative capacity was due to A 136 P or the other changes introduced in its backbone. Notably, a characterization of the viral quasispecies circulating in those animals in the chronic phase revealed that the A 136 P substitution did not revert to WT, indicating that it can be stably maintained in vivo in the absence of CD8 ϩ T-cell-mediated pressure (41). Based on these data, one might envision a scenario in which SIV initially tries to evade the host CD8 ϩ T-cell response by mutating the internal residues of Nef RL10, even though sequence variation within this highly conserved epitope is probably disadvantageous for the virus.…”

Section: Figmentioning

confidence: 99%

Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8 ⁺ T-Cell Responses Focused on a Single Nef Epitope Select for Escape Variants Shortly after Infection

Martins

Tully

Cruz

et al. 2015

J Virol

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Certain major histocompatibility complex class I (MHC-I) alleles (e.g., HLA-B*27) are enriched among human immunodeficiency virus type 1 (HIV-1)-infected individuals who suppress viremia without treatment (termed "elite controllers" [ECs]).Likewise, Mamu-B*08 expression also predisposes rhesus macaques to control simian immunodeficiency virus (SIV) replication. Given the similarities between Mamu-B*08 and HLA-B*27, SIV-infected Mamu-B*08؉ animals provide a model to investigate HLA-B*27-mediated elite control. We have recently shown that vaccination with three immunodominant Mamu-B*08-restricted epitopes (Vif RL8, Vif RL9, and Nef RL10) increased the incidence of elite control in Mamu-B*08 ؉ macaques after challenge with the pathogenic SIVmac239 clone. Furthermore, a correlate analysis revealed that CD8 ؉ T cells targeting Nef RL10 was correlated with improved outcome. Interestingly, this epitope is conserved between SIV and HIV-1 and exhibits a delayed and atypical escape pattern. These features led us to postulate that a monotypic vaccine-induced Nef RL10-specific CD8 ؉ T-cell response would facilitate the development of elite control in Mamu-B*08 ؉ animals following repeated intrarectal challenges with SIVmac239. To test this, we vaccinated Mamu-B*08؉ animals with nef inserts in which Nef RL10 was either left intact (group 1) or disrupted by mutations (group 2). Although monkeys in both groups mounted Nef-specific cellular responses, only those in group 1 developed Nef RL10-specific CD8 ؉ T cells. These vaccine-induced effector memory CD8 ؉ T cells did not prevent infection. Escape variants emerged rapidly in the group 1 vaccinees, and ultimately, the numbers of ECs were similar in groups 1 and 2. High-frequency vaccine-induced CD8 ؉ T cells focused on a single conserved epitope and therefore did not prevent infection or increase the incidence of elite control in Mamu-B*08 ؉ macaques. IMPORTANCESince elite control of chronic-phase viremia is a classic example of an effective immune response against HIV/SIV, elucidating the basis of this phenomenon may provide useful insights into how to elicit such responses by vaccination. We have previously established that vaccine-induced CD8 ؉ T-cell responses against three immunodominant epitopes can increase the incidence of elite control in SIV-infected Mamu-B*08؉ rhesus macaques-a model of HLA-B*27-mediated elite control. Here, we investigated whether a monotypic vaccine-induced CD8 ؉ T-cell response targeting the conserved "late-escaping" Nef RL10 epitope can increase the incidence of elite control in Mamu-B*08 ؉ monkeys. Surprisingly, vaccine-induced Nef RL10-specific CD8 ؉ T cells selected for variants within days after infection and, ultimately, did not facilitate the development of elite control. Elite control is, therefore, likely to involve CD8 ؉ T-cell responses against more than one epitope. Together, these results underscore the complexity and multidimensional nature of virologic control of lentivirus infection.

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“…In contrast, preferential targeting of the HIV envelope (Env) protein has been associated with higher viral loads in both human and monkey studies (17)(18)(19)(20). Although the precise mechanisms responsible for the enhanced antiviral function associated with Gag-specific responses are not fully understood, fitness costs associated with escape mutations from CD8 ϩ T cell responses directed at the highly conserved Gag protein have been implicated in both humans infected with HIV and primates infected with simian immunodeficiency virus (SIV) (21)(22)(23)(24)(25)(26)(27).…”

Section: Ost Human Immunodeficiency Virus (Hiv)-infected Individualmentioning

confidence: 99%

The Breadth of Expandable Memory CD8 ⁺ T Cells Inversely Correlates with Residual Viral Loads in HIV Elite Controllers

Ndhlovu

Stampouloglou

Cesa

et al. 2015

J Virol

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Previous studies have shown that elite controllers with minimal effector T cell responses harbor a low-frequency, readily expandable, highly functional, and broadly directed memory population. Here, we interrogated the in vivo relevance of this cell population by investigating whether the breadth of expandable memory responses is associated with the magnitude of residual viremia in individuals achieving durable suppression of HIV infection. HIV-specific memory CD8؉ T cells were expanded by using autologous epitopic and variant peptides. Viral load was measured by an ultrasensitive single-copy PCR assay. Following expansion, controllers showed a greater increase in the overall breadth of Gag responses than did untreated progressors (P ‫؍‬ 0.01) as well as treated progressors (P ‫؍‬ 0.0003). Nef-and Env-specific memory cells expanded poorly for all groups, and their expanded breadths were indistinguishable among groups (P ‫؍‬ 0.9 for Nef as determined by a Kruskal-Wallis test; P ‫؍‬ 0.6 for Env as determined by a Kruskal-Wallis test). More importantly, we show that the breadth of expandable, previously undetectable Gag-specific responses was inversely correlated with residual viral load (r ‫؍‬ ؊0.6; P ‫؍‬ 0.009). Together, these data reveal a direct link between the abundance of Gag-specific expandable memory responses and prolonged maintenance of low-level viremia. Our studies highlight a CD8 ؉ T cell feature that would be desirable in a vaccine-induced T cell response. IMPORTANCEMany studies have shown that the rare ability of some individuals to control HIV infection in the absence of antiretroviral therapy appears to be heavily dependent upon special HIV-specific killer T lymphocytes that are able to inhibit viral replication. The identification of key features of these immune cells has the potential to inform rational HIV vaccine design. This study shows that a special subset of killer lymphocytes, known as central memory CD8 ؉ T lymphocytes, is at least partially involved in the durable control of HIV replication. HIV controllers maintain a large proportion of Gag-specific expandable memory CD8 ؉ T cells involved in ongoing viral suppression. These data suggest that induction of this cell subset by future HIV vaccines may be important for narrowing possible routes of rapid escape from vaccine-induced CD8 ؉ T cell responses. M ost human immunodeficiency virus (HIV)-infected individuals have continuous viral replication and, if left untreated, eventually progress to AIDS (1-4). Only a very small group of infected individuals, referred to as elite controllers (EC)or elite suppressors, achieves spontaneous control of viral replication for prolonged periods in the absence of treatment (5-8). This remarkable control of viral replication among elite controllers is believed to be mediated largely by major histocompatibility complex (MHC) class I-restricted CD8 ϩ T cell responses (9-13). These individuals therefore present a unique model for understanding the in vivo mechanisms of T cell-mediated immune contr...

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CD8⁺T Cell Escape Mutations in Simian Immunodeficiency Virus SIVmac239 Cause Fitness DefectsIn Vivo, and Many Revert after Transmission

Cited by 13 publications

References 45 publications

HIV and HLA Class I: An Evolving Relationship

HIV and HLA Class I: An Evolving Relationship

Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8 ⁺ T-Cell Responses Focused on a Single Nef Epitope Select for Escape Variants Shortly after Infection

The Breadth of Expandable Memory CD8 ⁺ T Cells Inversely Correlates with Residual Viral Loads in HIV Elite Controllers

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CD8+T Cell Escape Mutations in Simian Immunodeficiency Virus SIVmac239 Cause Fitness DefectsIn Vivo, and Many Revert after Transmission

Cited by 13 publications

References 45 publications

HIV and HLA Class I: An Evolving Relationship

HIV and HLA Class I: An Evolving Relationship

Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8 + T-Cell Responses Focused on a Single Nef Epitope Select for Escape Variants Shortly after Infection

The Breadth of Expandable Memory CD8 + T Cells Inversely Correlates with Residual Viral Loads in HIV Elite Controllers

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Product

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CD8⁺T Cell Escape Mutations in Simian Immunodeficiency Virus SIVmac239 Cause Fitness DefectsIn Vivo, and Many Revert after Transmission

Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8 ⁺ T-Cell Responses Focused on a Single Nef Epitope Select for Escape Variants Shortly after Infection

The Breadth of Expandable Memory CD8 ⁺ T Cells Inversely Correlates with Residual Viral Loads in HIV Elite Controllers