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

Abstract

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...

Preservation of Lymphopoietic Potential and Virus Suppressive Capacity by CD8+ T Cells in HIV-2–Infected Controllers

“…However, we have previously shown that suppressive CD8 T cell activity in HIV-1 controllers remained low in some donors even when autologous virus was used (39). Alternatively, the absence of suppressive activity may be a consequence of the stringent control of viremia, resulting in the contraction of the HIV-2-specific CD8 + T cell response to a small pool of high-quality memory cells that fall below the detection threshold of our assay (49,52,53). Moreover, we were only able to analyze the CD8 + T cell response in blood and would not be able to measure more robust responses that were active locally in patient tissues (54).…”

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Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

“…This phenomenon may be particularly relevant and efficient in the long term in HICs, whose target cells are also strongly resistant to HIV-1 infection, particularly at low infectious doses (17,40), providing an additional barrier to viral amplification. In addition, weakly responsive memory CD8 ϩ T cells in HICs are ready to react and expand promptly in response to stochastic viral amplification events (12,50) (Fig. 5C), thereby ensuring natural control of HIV-1 infection in the very long term.…”