Reservoirs of drug-resistant HIV-1

Frenkel, Lisa

Abstract

Treatment of HIV-1 infection with highly active antiretroviral therapy (HAART) can markedly improve immune function and general health. However, a significant proportion of HIV-1 infected individuals do not fully benefit from antiretroviral treatment due to the selection of drug-resistant virus. Once selected, drug-resistant virus persists, often at undetectable levels, but limiting the efficacy of subsequent treatments with either the same or alternate regimens due to the substantial cross-resistance. Our knowledge regarding the establishment and persistence of reservoirs of drug-resistant virus is incomplete, however, it is these reservoirs that we need to understand and overcome for successful treatment of a large segment of the HIV-l-infected population. We hypothesize that pulmonary (and probably other) macrophages are the principal long-term reservoir of drug-resistant virus; that the long-lived viral reservoir is for the most part established during primary infection; that short-lived lymphocytes comprise a temporary reservoir of drug-resistant virus; and that the turnover of HIV-1 infected cells that comprise short-term viral reservoirs occurs in a timeframe that is clinically relevant. To test these hypotheses, we propose to identify reservoirs of drug-resistant virus, study their persistence, and learn how these reservoirs impact the efficacy of HAART:
Aim 1 : Define the tissue and cellular reservoirs of drug-resistant HIM-I Viral sequences from sequential specimens of blood plasma and peripheral blood mononuclear cells (PBMC) collected from perinatally infected children during mono- and dual-therapy will be compared to sequences from pulmonary macrophages and blood during HAART, and similarly, sequential blood specimens will be compared to those in autopsy tissues; tracking drug resistance mutations and phylogenetic lineages to establish compartmentalized tissues and long-lived reservoirs of HIV-1 infection.
Aim 2 : Determine when long-lived viral reservoirs are established and how they are perturbed by antiviral selective pressure Genotypic drug-resistance markers will be used to gauge the persistence and turnover of virus acquired during primary infection compared to virus selected at a later date. The persistence of nevirapine-resistant viral variants in infants who are infected during chemoprophylaxis (most likely with drug-resistant HIV-1) will be compared to the decay of mutants in infants infected in utero with wild-type HIV-1 in whom drug-resistant mutants are subsequently selected by antiretroviral chemoprophylaxis.
Aim 3 : Quantify the selection of nevirapine-resistant virus by HAART administered by directly observed therapy (DOT) in individuals who did and did not receive peripartum nevirapine in the past for infant chemoprophylaxis The decay in clinically significant mutants selected by single-dose nevirapine will be gauged by determining if nevirapine-resistant virus selected by DOT-HAART varies by the time interval between the administration of peripartum nevirapine and initiation of DOT-HAART. The proposed studies should provide insight into the establishment and persistence of drug-resistant viral reservoirs, and thereby provide the understanding needed to avoid the establishment of drug-resistant virus in these reservoirs through modification of therapeutic protocols.