Abstract
Multiple lines of evidence indicate that CD8 T cells are important in the control of HIV-1 (HIV) replication. However, CD8 T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8 T-cell responses induced during HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8 T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8 T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8 T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8 T cells in the chronic infection. The breadth of HIV-specific CD8 T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8 T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8 T-cell responses and the presence of intra- and interclonal competition between multiple CD8 T-cell responses; such competition may limit the magnitude of CD8 T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8 T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.
Highlights
HIV-1 (HIV) remains a major global infectious disease with more than 35 million infected individuals, and millions of deaths due to AIDS every year [1,2]
While some HIV-infected individuals do not appear to progress to AIDS and maintain high CD4+ T-cell counts in their peripheral blood, whether CD8+ T cells are solely responsible for such control remains undetermined [46,49,50,51,52,53]
While CD8+ T-cell responses are thought to play an important role in control of HIV replication, the kinetics of CD8+ T-cell responses specific to most HIV proteins, especially during the acute phase of infection, have not been quantified
Summary
HIV-1 (HIV) remains a major global infectious disease with more than 35 million infected individuals, and millions of deaths due to AIDS every year [1,2]. A highly effective vaccine against HIV/AIDS is not yet available; several vaccine candidates failed in large phase II or III clinical trials [3,4,5] One set of such failed trials investigated the efficacy of a CD8+ T-cell-based vaccine against HIV that had shown reasonable protection following the infection of immunized monkeys with SIV [6,7]. Some vaccination protocols in monkeys, in which high levels of SIV-specific CD8+ T cells were induced, resulted in a reduced viral load and, under certain conditions, apparent elimination of the virus [6,7,41,42,43,44] Despite these promising experimental observations, following natural infection, CD8+ T-cell responses have not cleared HIV in any patient, or reduced viral loads to acceptably low levels in many individuals [16,45,46]. If induction of a broad (i.e., specific to multiple epitopes) and high magnitude CD8+
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