Rapid communication: development of in vitro resistance to macrophage-tropic- and T-cell-line-adapted HIV-1 strains among HIV-positive volunteers treated with highly active antiretroviral therapy.
We have described a peripheral blood mononuclear cell (PBMC) culture system in which control of endogenous virus and resistance to exogenous HIV-1 correlates with low viremia among HIV-1-positive people. Nineteen patients remained consistently resistant or susceptible for more than 5 years of follow-up. On the fifth year, 5 consistently susceptible volunteers with high viral loads began receiving highly active anti-retroviral therapy (HAART). After >6 months on HAART, 5 of 5 became completely or predominantly resistant on four visits over the next 6 months. Among HIV-1-positive donors, we had never observed reversal of PBMC phenotype from consistently susceptible to consistently resistant. Resistance correlated with suppression of plasma viremia and rebound in CD4+ T-cell counts and percentages. When resistant PBMCs were challenged after CD8+ T-cell depletion, 38 of 41 and 40 of 59 cultures became susceptible to HIV-1MN and HIV-1BaL, respectively. After combined CD8+ T-cell depletion and antibody neutralization of beta-chemokines, 16 of 18 cultures became susceptible to HIV-1BaL. Overall, the finding that >90% of these cultures depleted of relevant antiviral effector arms could become infected indicates resistance was not due to residual antiretroviral drug metabolites in vitro. For 2 volunteers who discontinued therapy because of side effects, pretreatment viral load correlated with loss of in vitro resistance and viral rebound. In addition to resistance to laboratory strains of HIV-1, all patients developed resistance to at least one of two CCR5-tropic, clade B primary isolates: HIV-1P15 and HIV-1P27.
Castillo
R C
RC
Department of Molecular Microbiology and Immunology, The Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Maryland 21205, USA.
Arango-Jaramillo
S
S
John
R
R
Turner
B C
BC
Zimmerman
E
E
Schwartz
D H
DH
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000906:Antibodies / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000276:immunology; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D016655:HIV Core Protein p24 / Q000032:analysis; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects* / Q000821:virology; D013375:Substance Withdrawal Syndrome / Q000276:immunology; D019562:Viral Load; D014766:Viremia
D019380:Anti-HIV Agents; D000906:Antibodies; D018925:Chemokines; D016655:HIV Core Protein p24