Productive Infection Maintains a Dynamic Steady State of Residual Viremia in Human Immunodeficiency Virus Type 1-Infected Persons Treated with Suppressive Antiretroviral Therapy for Five Years

Abstract

To provide insight into the dynamics and source of residual viremia in human immunodeficiency virus (HIV) patients successfully treated with antiretroviral therapy, 14 intensely monitored patients treated with indinavir and efavirenz sustaining HIV RNA at <50 copies/ml for >5 years were studied. Abacavir was added to the regimen of eight patients at year 5. After the first 9 months of therapy, HIV RNA levels had reached a plateau ("residual viremia") that persisted for over 5 years. Levels of residual viremia differed among patients and ranged from 3.2 to 23 HIV RNA copies/ml. Baseline HIV DNA was the only significant pretreatment predictor of residual viremia in regression models including baseline HIV RNA, CD4 count, and patient age. In the four of five patients with detectable viremia who added abacavir to their regimen after 5 years, HIV RNA levels declined rapidly. The estimated half-life of infected cells was 6.7 days. Decrease in activated memory cells and a reduction in gamma interferon production to HIV Gag and p24 antigen in ELISpot assays were observed, consistent with a decrease in HIV replication. Thus, in patients treated with efavirenz plus indinavir, levels of residual viremia were established by 9 months, were predicted by baseline proviral DNA, and remained constant for 5 years. Even after years of highly suppressive therapy, HIV RNA levels declined rapidly after the addition of abacavir, suggesting that productive infection contributes to residual ongoing viremia and can be inhibited with therapy intensification.

R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L−CD4+T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors

“…The same results were obtained with resting T cells from PBMCs of viremic patients (14,27,33,34). Resistance of HIV-1 replication to antiretroviral drugs in resting memory CD4 ϩ T cells of infected individuals highlights an urgent need to search for new HIV therapies.…”

“…Later, in many cases, CXCR4-utilizing variants (X4 variants) evolve and are associated with depletion of CD4 ϩ T cells and with a rapid progression to AIDS. Recent studies have clearly established that infection with HIV-1 predominantly occurs in CD4 ϩ memory T cells (8,14,27,29,47,51,57,67). Memory cells comprise several subsets defined by differential expression of CD45RA, CD45RO, homing receptors, and activation markers (16,35,41,52).…”

HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir

“…These include the persistence of replication-competent virus (2-4), unintegrated proviral DNA, both linear (2) and circularized (13,14), and cell-associated HIV RNA (6,7,11,15,16). In addition, other studies have demonstrated that intensification of conventional antiviral regimens in patients who remained aviremic accelerated the decay of the latent HIV reservoir in the resting CD4 + T cell compartment (12) and further suppressed plasma viremia to well below the limit of detection (3.2-23 copies of HIV RNA per ml) (17). These findings suggest that low levels of ongoing HIV replication continue to persist and may contribute to the longevity of the latent viral reservoir by continually fueling new rounds of infection in resting CD4 + T cells.…”

A viral load-based cellular automata approach to modeling HIV dynamics and drug treatment

“…Recent studies have shown that a pool of latently infected cells is established during the primary phase of HIV infection (Bonhoeffer et al, 1997;Grossman et al, 1998;Havlir et al, 2003;Lafeuillade et al, 2000;Muller et al, 2002). These cells are infected cells in a resting state and can be activated after a long time of dormancy to produce infectious virus particles.…”