Residual Proviral Reservoirs: A High Risk for HIV Persistence and Driving Forces for Viral Rebound after Analytical Treatment Interruption

Abstract

Antiretroviral therapy (ART) has dramatically suppressed human immunodeficiency virus (HIV) replication and become undetectable viremia. However, a small number of residual replication-competent HIV proviruses can still persist in a latent state even with lifelong ART, fueling viral rebound in HIV-infected patient subjects after treatment interruption. Therefore, the proviral reservoirs distributed in tissues in the body represent a major obstacle to a cure for HIV infection. Given unavailable HIV vaccine and a failure to eradicate HIV proviral reservoirs by current treatment, it is crucial to develop new therapeutic strategies to eliminate proviral reservoirs for ART-free HIV remission (functional cure), including a sterilizing cure (eradication of HIV reservoirs). This review highlights recent advances in the establishment and persistence of HIV proviral reservoirs, their detection, and potential eradication strategies.

Early treatment regimens achieve sustained virologic remission in infant macaques infected with SIV at birth

“…Near full-length individual proviral sequencing and intact proviral DNA assay (IPDA) also may not accurately distinguish the functional viral reservoir, as indicated by existence of intact proviral quasispecies and viral polymorphism 52 , 53 , the difficulties inherent in predicting the production of replication-competent virions in the viral life cycle of HIV/SIV, questionable functionality of viral genomes by various Indels and mutations 47 , 54 – 56 , or potential functional revertant mutations from deficient viral genomes 57 , 58 . Therefore, there is no gold standard approach to assess the genuine size of viral reservoirs in the body because of limited tissue sampling, and sensitivity limitations 59 . Although qPCR may overestimate the viral reservoirs because of defective proviruses, total proviral DNA levels can still estimate the size of the intact viral genome, which accounts for ~11.7% in HIV+ patients and even higher fractions in SIV+ macaques on cART 60 , 61 .…”

Early Treatment Regimens Achieve Sustained Virologic Remission in Infant Macaques Infected with SIV at Birth

“…Viral reservoirs examined by Quantitative Viral Outgrowth Assays (QVOA) or Tat/rev Induced Limiting Dilution Assays (TILDA) may not fully reactivated by stimulators, especially when the proviruses are located in the "gene desert" sites of chromosomes enriched in repressive chromatin marks 45,49,50,51 . Near full-length Individual proviral sequencing (FLIPS) and intact proviral DNA assay (IPDA) may also not accurately distinguish the functional proviral reservoir, as indicated by existence of intact proviral "quasispecies" and viral polymorphism 52,53 , di culties to predict production of replication-competent virions in the process of viral life cycle of HIV/SIV, functionality of viral genomes by various depletions and mutations 47,54,55,56 , or potential functional revertant mutation from de cient viral genome 57,58 , thereby lack of absolute gold standard approach to assess the genuine size of proviral reservoirs in the body 59 . Although qPCR may overestimate the viral reservoirs because of defective proviruses, total proviral DNA levels still re ects approximate size of intact viral genome, as intact viral genome accounts for ~11.7% in HIV+ patients and exists with higher fraction in SIV+ macaques on cART 60,61 .…”

Systemic and Intestinal Viral Reservoirs in CD4+ T Cell Subsets in Primary SIV Infection

“…In comparison, qPCR can provide a rapid and sensitive approach to estimate the viral reservoir seeding and size in various tissues, generating comparable data despite overestimating the viral reservoirs due to the existence of defective proviruses. There is no absolute gold standard approach to assess the actual size of viral reservoirs in the body thus far [32].…”