Why the HIV Reservoir Never Runs Dry: Clonal Expansion and the Characteristics of HIV-Infected Cells Challenge Strategies to Cure and Control HIV Infection

Abstract

Antiretroviral therapy (ART) effectively reduces cycles of viral replication but does not target proviral populations in cells that persist for prolonged periods and that can undergo clonal expansion. Consequently, chronic human immunodeficiency virus (HIV) infection is sustained during ART by a reservoir of long-lived latently infected cells and their progeny. This proviral landscape undergoes change over time on ART. One of the forces driving change in the landscape is the clonal expansion of infected CD4 T cells, which presents a key obstacle to HIV eradication. Potential mechanisms of clonal expansion include general immune activation, antigenic stimulation, homeostatic proliferation, and provirus-driven clonal expansion, each of which likely contributes in varying, and largely unmeasured, amounts to maintaining the reservoir. The role of clinical events, such as infections or neoplasms, in driving these mechanisms remains uncertain, but characterizing these forces may shed light on approaches to effectively eradicate HIV. A limited number of individuals have been cured of HIV infection in the setting of bone marrow transplant; information from these and other studies may identify the means to eradicate or control the virus without ART. In this review, we describe the mechanisms of HIV-1 persistence and clonal expansion, along with the attempts to modify these factors as part of reservoir reduction and cure strategies.

Persistence of Unintegrated HIV DNA Associates With Ongoing NK Cell Activation and CD34+DNAM-1brightCXCR4+ Precursor Turnover in Vertically Infected Patients Despite Successful Antiretroviral Treatment

“…In addition, clonal expansion directed towards diverse antigens including CMV, flu, EBV rather than passive expansion could represent an important aspect in reservoir maintenance. Depending on efficiency of translocation, viral replication, innate immune mechanisms and CD8+CTL function, variable CD4 clonal expansion could be envisaged, with different levels of involvement of NK cells to control the renovating reservoir ( 64 ).…”

HIV DNA Sequencing to Detect Archived Antiretroviral Drug Resistance

“…Such variants can integrate as proviral DNA, thus seeding the viral reservoir [5,6]. Proliferation of CD4 T-cells harbouring integrated virus, either homeostatic or as a result of antigenic stimulation, is thought to maintain the size of the HIV reservoir through many years of virologically suppressive ART [7][8][9][10]. Archived RAMs can re-emerge if virus production resumes, facilitated by lapses in adherence or treatment interruption, retaining potential clinical significance long term.…”

Current strategies to induce selective killing of HIV-1-infected cells

“…These include the viral cytopathic effect, immune clearance, and clonal expansion of latent HIV‐1‐infected CD4+ T cells 25,26 . The precise mechanism(s) by which latent HIV‐1‐infected cell clonal expansion occurs are not completely understood, but are thought to include general immune activation, antigen driven expansion and contraction of infected CD4+ T cell clones, homeostatic proliferation, and HIV‐1 integration site‐dependent provirus‐driven clonal expansion 4,11,19,27–33 …”

“…25,26 The precise mechanism(s) by which latent HIV-1infected cell clonal expansion occurs are not completely understood, but are thought to include general immune activation, antigen driven expansion and contraction of infected CD4+ T cell clones, homeostatic proliferation, and HIV-1 integration site-dependent provirus-driven clonal expansion. 4,11,19,[27][28][29][30][31][32][33] Although ART suppresses HIV-1 replication, improves immune function, reduces comorbidities, and has led to significant improvements in both longevity and quality of life in PLWH, it does not completely reverse the significant loss in virus-specific immune functions observed in PLWH, 34 nor does it eliminate the preexisting HIV-1 reservoir. 24 Additionally, ART presents challenges such as adherence to drug regimens, the emergence of resistant viruses, and cumulative ART toxicity.…”