Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy.
BACKGROUND
In patients infected with human immunodeficiency virus type 1 (HIV-1), combination antiretroviral therapy can result in sustained suppression of plasma levels of the virus. However, replication-competent virus can still be recovered from latently infected resting memory CD4 lymphocytes; this finding raises serious doubts about whether antiviral treatment can eradicate HIV-1.


METHODS
We looked for evidence of residual HIV-1 replication in eight patients who began treatment soon after infection and in whom plasma levels of HIV-1 RNA were undetectable after two to three years of antiretroviral therapy. We examined whether there had been changes over time in HIV-1 proviral sequences in peripheral-blood mononuclear cells, which would indicate residual viral replication. We also performed in situ hybridization studies on tissues from one patient to identify cells actively expressing HIV-1 RNA. We estimated the rate of decrease of latent, replication-competent HIV-1 in resting CD4 lymphocytes on the basis of the decrease in the numbers of proviral sequences identified during primary infection and direct sequential measurements of the size of the latent reservoir.


RESULTS
Six of the eight patients had no significant variations in proviral sequences during treatment. However, in two patients there was sequence evolution but no evidence of drug-resistant viral genotypes. In one patient, extensive in situ studies provided additional evidence of persistent viral replication in lymphoid tissues. Using two independent approaches, we estimated that the half-life of the latent, replication-competent virus in resting CD4 lymphocytes was approximately six months.


CONCLUSIONS
These findings suggest that combination antiretroviral regimens suppress HIV-1 replication in some but not all patients. Given the half-life of latently infected CD4 lymphocytes of about six months, it may require many years of effective antiretroviral treatment to eliminate this reservoir of HIV-1.
Zhang
L
L
Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY 10016, USA.
Ramratnam
B
B
Tenner-Racz
K
K
He
Y
Y
Vesanen
M
M
Lewin
S
S
Talal
A
A
Racz
P
P
Perelson
A S
AS
Korber
B T
BT
Markowitz
M
M
Ho
D D
DD
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001483:Base Sequence; D004359:Drug Therapy, Combination; D015752:Genes, env; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D006801:Humans; D017403:In Situ Hybridization; D016018:Least-Squares Analysis; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D012367:RNA, Viral