Persistence of HIV in Gut‐Associated Lymphoid Tissue despite Long‐Term Antiretroviral Therapy

Abstract

Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistent HIV in such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4(+) T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4(+) T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4(+) T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around the GALT of HIV-infected individuals despite long-term viral suppression and suggest that the GALT may play a major role in the persistence of HIV in such individuals.

Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9

“…Although the introduction of effective antiretroviral therapy (ART) has resulted in huge reductions in rates of human immunodeficiency virus type 1 (HIV-1) illness, HIV-1 infection remains incurable. In addition, ART encounters a number of challenges, including a persistent latent viral reservoir, the requirement for lifelong adherence, and the potential development of drug resistance and toxicity (Chun et al, 2008;Corbeau & Reynes, 2011;Kent et al, 2013;Richman et al, 2009;Sendagire et al, 2009). Thus the development of novel therapeutic methods that may enhance current therapeutic options and even lead to curative approaches would significantly expand our portfolio of strategies to counteract HIV-1/AIDS.…”

Preferential loss of gut-homing α4β7 CD4+ T cells and their circulating functional subsets in acute HIV-1 infection

“…4,5 This loss is not easily reversible despite long-term successful antiretroviral therapy (ART). [6][7][8][9] HIV/SIV infection also reduces Th17 cells and impairs gut mucosal integrity, which results in microbial translocation and high levels of immune activation and systemic inflammation in HIV/SIV-infected individuals. [10][11][12][13][14] Alterations in Th17:Th1 and Th17:Treg balance also contribute to disease progression in HIV/SIV infection.…”

The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

“…Several studies, however, suggest that the reservoir is largely established and maintained in lymphoid tissues, and that the infected cells circulating in blood may not be representative of the population of infected cells in tissue. For example, the majority of lymphocytes are sequestered in the gastrointestinal tract, and gutassociated lymphoid tissue (GALT) has been shown to be a major viral reservoir in patients on suppressive antiretroviral therapy (17)(18)(19)(20)(21)(22).…”