[28] CHARACTERIZATION OF HIV-1 EVOLUTION AND DYNAMICS IN PERIPHERAL BLOOD MONONUCLEAR CELLS DURING EFFECTIVE HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

5th International Workshop on HIV Drug Resistance & Treatment Strategies

4-8 June 2001, Scottsdale, Arizona

[TITLE:] CHARACTERIZATION OF HIV-1 EVOLUTION AND DYNAMICS IN PERIPHERAL BLOOD MONONUCLEAR CELLS DURING EFFECTIVE HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

[AUTHOR(S):] LM Frenkel¹, Y Wang¹, AJ Melvin¹, SM DeVange¹, JL McKernan¹, GM Ellis¹, KM Mohan¹, GL Sylva¹, L Heath¹, M Mahalanabis¹, WE Naugler¹, I Beck¹, P Lewis², GH Learn¹ and JI Mullins¹
¹ University of Washington, Seattle, Wash., USA; and ² Oregon Health Sciences University, Portland, Oreg., USA
Antivir Ther. 2001;6 Suppl 1:23

OBJECTIVE: To characterize the magnitude of HIV-1 replication and evolution that occurs during apparently effective highly active antiretroviral therapy (HAART).

METHODS: The HIV-1 peripheral blood mononuclear cells (PBMC) quasi-species were evaluated at intervals before and during HAART that suppressed plasma HIV-1 RNA to <500 through 1997 followed by <50 copies/ml. Ten or more pol and env amplicons were sequenced directly from PBMC or plasma dilutions with a high probability of having only one HIV-1 template.

RESULTS: Phylogenetic analyses of env and pol from nine children before and during a median of 4 years (range 2–5 years) of effective HAART indicated that recently infected cells diminished in number. The persisting cell-associated HIV-1 grouped primarily with virus from early in infection. This persisting ‘early virus’ was not solely defective as it was occasionally expressed at low levels (5–236 copies/ml) in the plasma. A continuum of replication could be distinguished during effective HAART. No evolution was detected in 6/9 phylograms and genetic distances from the most recent common ancestor decreased during five-drug HAART; in three of these there was a diminution of HIV-1 PBMC DNA >1 log₁₀. The remaining 3/9 had detectable evolution in their phylograms; during three-drug HAART, two had selection of new resistance mutations preceding rebound of plasma HIV-1 RNA to >500 copies/ml. After intensification to five-drug HAART, one of these two continued to show selection for drug resistance mutations to all three classes of antiretrovirals, but maintained RNA <50–101 copies/ml for 4 years, and ultimately <50 copies/ml with additional HAART intensification.

CONCLUSIONS: The majority of long-lived infected PBMC have virus that appear to be from near the time of primary infection. The low-levels of HIV-1 replication detected by various research assays during HAART may not have clinical consequences, or may lead to selection of drug-resistant virus. The potency of the HAART regimen may determine whether viral replication is suppressed sufficiently to prevent the selection of fit drug-resistant virus. Individuals without viral evolution could be identified by marked decreases in HIV-1 DNA copy number and a narrowing of the genetic distance of env and pol to the most recent common ancestor after initiating HAART.

PRESENTING AUTHOR: LM Frenkel

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