CD4+T Cell Kinetics and Activation in Human Immunodeficiency Virus–Infected Patients Who Remain Viremic Despite Long‐Term Treatment with Protease Inhibitor–Based Therapy (original) (raw)
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The Journal of Infectious Diseases, 2002
T cell dynamics were studied in human immunodeficiency virus-infected patients who continued using antiretroviral therapy despite detectable plasma viremia (RNA copies >2500 /mL). CD4 + cell fractional replacement rates, measured by the deuterated glucose technique, were lower in treated patients with detectable viremia than in untreated patients and were similar to those in patients with undetectable viremia. Cell cycle and activation markers exhibited similar trends. For any level of viremia, CD4 + cell fractional replacement rates were lower in patients with drug-resistant virus than in patients with wild-type virus, which suggests that the resistant variant was less virulent. Interruption of treatment in patients with drug-resistant viremia resulted in increased CD4 + cell activation, increased CD4 + cell turnover, and decreased CD4 + cell counts. These data indicate that partial virus suppression reduces CD4 + cell turnover and activation, thereby resulting in sustained CD4 + cell gains, and that measurements of T cell dynamics may provide an in vivo marker of viral virulence.
Journal of Virology, 2009
A stable latent reservoir for human immunodeficiency virus type 1 (HIV-1) in resting memory CD4 ؉ T cells presents a barrier to eradication of the infection even in patients on highly active antiretroviral therapy. Potential mechanisms for latency include inaccessibility of the integrated viral genome, absence of key host transcription factors, premature termination of HIV-1 RNAs, and abnormal splicing patterns. To differentiate among these mechanisms, we isolated extremely pure populations of resting CD4 ؉ T cells from patients on highly active antiretroviral therapy. These cells did not produce virus but retained the capacity to do so if appropriately stimulated. Products of HIV-1 transcription were examined in purified resting CD4 ؉ T cells. Although short, prematurely terminated HIV-1 transcripts have been suggested as a marker for latently infected cells, the production of short transcripts had not been previously demonstrated in purified populations of resting CD4 ؉ T cells. By separating RNA into polyadenylated and nonpolyadenylated fractions, we showed that resting CD4 ؉ T cells from patients on highly active antiretroviral therapy produce abortive transcripts that lack a poly(A) tail and that terminate prior to nucleotide 181. Short transcripts dominated the pool of total HIV-1 transcripts in resting CD4 ؉ T cells. Processive, polyadenylated HIV-1 mRNAs were also present at a low level. Both unspliced and multiply spliced forms were found. Taken together, these results show that the nonproductive nature of the infection in resting CD4 ؉ T cells from patients on highly active antiretroviral therapy is not due to absolute blocks at the level of either transcriptional initiation or elongation but rather relative inefficiencies at multiple steps.
The Journal of Infectious Diseases, 1999
Biphasic plasma viral decays were modeled in 48 patients treated with ritonavir, zidovudine, and lamivudine. Estimated first-and second-phase decay rates were d 1 as 0.47/day and d 2 as 0.04/day. Interpatient differences in both decay rates were significant. The d 1 was directly correlated with baseline CD4 + , CD4 + CD28 + , and CD8 + CD28 + T lymphocyte counts (P ! ) and inversely correlated with baseline virus load ( ) and the magnitude of CD4 + .05 P ϭ .044 and CD8 + T lymphocyte recovery ( ). The d 2 was directly correlated with base-P ! .01 line percentage of CD8 + T lymphocytes ( ), the CD8 + CD38 + cell number ( ), P ϭ .023 P ϭ .024 and the level of IgG that binds to human immunodeficiency virus (HIV) type 1 gp120 (P ϭ ). Viral decay rates were not predictive of treatment failure or durability of viral suppression. .02 These exploratory findings are consistent with a model in which immunologic factors contribute to elimination of HIV-infected cells and suggest a dynamic interplay between regulation of HIV expression and lymphocyte activation and recovery.
Journal of Virology, 2003
patients successfully treated with antiretroviral therapy, 14 intensely monitored patients treated with indinavir and efavirenz sustaining HIV RNA at <50 copies/ml for >5 years were studied. Abacavir was added to the regimen of eight patients at year 5. After the first 9 months of therapy, HIV RNA levels had reached a plateau ("residual viremia") that persisted for over 5 years. Levels of residual viremia differed among patients and ranged from 3.2 to 23 HIV RNA copies/ml. Baseline HIV DNA was the only significant pretreatment predictor of residual viremia in regression models including baseline HIV RNA, CD4 count, and patient age. In the four of five patients with detectable viremia who added abacavir to their regimen after 5 years, HIV RNA levels declined rapidly. The estimated half-life of infected cells was 6.7 days. Decrease in activated memory cells and a reduction in gamma interferon production to HIV Gag and p24 antigen in ELISpot assays were observed, consistent with a decrease in HIV replication. Thus, in patients treated with efavirenz plus indinavir, levels of residual viremia were established by 9 months, were predicted by baseline proviral DNA, and remained constant for 5 years. Even after years of highly suppressive therapy, HIV RNA levels declined rapidly after the addition of abacavir, suggesting that productive infection contributes to residual ongoing viremia and can be inhibited with therapy intensification.
The Journal of Infectious Diseases, 2003
Mechanisms that underly discordant CD4 + cell/virus load (VL) responses in patients who receive highly active antiretroviral therapy (HAART) were studied in 30 human immunodeficiency virus (HIV)-positive patients, in 3 groups. Discordant responders maintained CD4 + cell levels 1200/mm 3 with stable or increasing trend, despite sustained VLs of 500-5000 copies/mL, for 12 years. Treatment-success patients had CD4 + cell counts 1200/mm 3 with stable or increasing trend and VLs !50 copies/mL, for 12 years. Treatment-failure patients initially responded to HAART, followed by decreasing CD4 + cell counts and increasing VLs. Interferon-g production to gag and noncytolytic CD8 + cell suppressive activity were greater in discordant responders. Cellular activation was greatest in patients with treatment failure. All discordant responders had non-syncytium-inducing (CCR5-tropic) viruses. Viruses from discordant responders and from patients with treatment failure had extensive resistance mutations; discordant responders had significantly lower viral replication capacities. These findings suggest that discordant responses may be related to enhanced HIV-directed immune responses, diminished cellular activation, decreased viral replication capacity, and preservation of non-syncytium-inducing virus strains. Although current treatment guidelines stress the importance of the suppression of human immunodeficiency virus (HIV)-1 virus load (VL) below 50 copies/ mL [1], not all patients are able to achieve or sustain this response with highly active antiretroviral therapy (HAART) [2-6]. Among patients who achieved undetectable VLs in the Swiss HIV Cohort study, 20% of treatment-naive and 35%-40% of treatment-experienced patients had virus rebound within 2 years [4].
Journal of Virology, 2005
The human immunodeficiency virus (HIV)-mediated immune response may be beneficial or harmful, depending on the balance between expansion of HIV-specific T cells and the level of generalized immune activation. The current study utilizes multicolor cytokine flow cytometry to study HIV-specific T cells and T-cell activation in 179 chronically infected individuals at various stages of HIV disease, including those with low-level viremia in the absence of therapy (“controllers”), low-level drug-resistant viremia in the presence of therapy (partial controllers on antiretroviral therapy [PCAT]), and high-level viremia (“noncontrollers”). Compared to noncontrollers, controllers exhibited higher frequencies of HIV-specific interleukin-2-positive gamma interferon-positive (IL-2 + IFN-γ + ) CD4 + T cells. The presence of HIV-specific CD4 + IL-2 + T cells was associated with low levels of proliferating T cells within the less-differentiated T-cell subpopulations (defined by CD45RA, CCR7, CD27, a...
Journal of Virology, 2004
The meaning of viral blips in human immunodeficiency virus type 1 (HIV-1)-infected patients treated with seemingly effective highly active antiretroviral therapy (HAART) is still controversial and under investigation. Blips might represent low-level ongoing viral replication in the presence of drug or simply release of virions from the latent reservoir. Patients treated early during HIV-1 infection are more likely to have a lower total body viral burden, a homogenous viral population, and preserved HIV-1-specific immune responses. Consequently, viral blips may be less frequent in them than in patients treated during chronic infection. To test this hypothesis, we compared the occurrence of viral blips in 76 acutely infected patients (primary HIV infection [PHI] group) who started therapy within 6 months of the onset of symptoms with that in 47 patients who started HAART therapy during chronic infection (chronic HIV infection [CHI] group). Viral blip frequency was approximately twofol...