Broad spectrum cytolytic T lymphocytes response is required to clear latent HIV-1 due to dominance of escape mutations

HIV-1;latent reservoir;antiretroviral drugs;cytolytic T lymphocytes;escape mutation;Immunology

Deng, KaiHendrix, Craig W. ;

Johns Hopkins University

关键词: HIV-1;    latent reservoir;    antiretroviral drugs;    cytolytic T lymphocytes;    escape mutation;    Immunology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39275/DENG-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Highly active antiretroviral therapy (HAART) can suppress HIV-1 replication, but fails to eradicate the infection. For chronically infected individuals, life-long treatment is required to prevent disease progression to acquired immunodeficiency syndrome (AIDS). A comparative measure of antiviral activity under clinically relevant conditions would guide drug development and selection of regimens that maximally suppress replication. Simian immunodeficiency virus (SIV) infection in macaques is so far the best animal model for human immunodeficiency virus type 1 (HIV-1) studies, but suppressing viral replication in infected animals remains challenging. Using a novel single-round infectivity assay, we quantitated the antiviral activities of antiretroviral drugs against SIV. Our results emphasize the importance of the dose-response curve slope in determining the inhibitory potential of antiretroviral drugs and provide useful information for regimen selection in treating SIV-infected animals in models of therapy and virus eradication.Despite HAART, HIV-1 persists in a stable latent reservoir, primarily in resting memory CD4+ T cells. This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed and tested both in vitro and in vivo. The next step is to eliminate the resting CD4+ T cells in which latent HIV-1 has been induced through virus-specific immune mechanisms including cytolytic T lymphocytes (CTL). A key question is whether antiviral immune responses in patients on ART can clear infected cells after latency is reversed. We show here that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. The vast majority (>98%) of latent viruses carry CTL escape mutations that render the infected cells insensitive to CTLs directed at common epitopes. To solve this critical problem, we identified CTLs that could recognize antigens from latent HIV-1 that were unmutated in every chronically infected patient tested. We further demonstrated that these CTLs were able to eliminate target cells infected with autologous virus derived from the latent reservoir. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.