HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression

Identifying the immunologic and virologic consequences of discontinuing antiretroviral therapy in HIV-infected patients is of major importance in developing long-term treatment strategies for patients with HIV-1 infection. We designed a trial to characterize these parameters after interruption of highly active antiretroviral therapy (HAART) in patients who had maintained prolonged viral suppression on antiretroviral drugs. Eighteen patients with CD4+ T cell counts ≥ 350 cells/μl and viral load below the limits of detection for ≥1 year while on HAART were enrolled prospectively in a trial in which HAART was discontinued. Twelve of these patients had received prior IL-2 therapy and had low frequencies of resting, latently infected CD4 cells. Viral load relapse to >50 copies/ml occurred in all 18 patients independent of prior IL-2 treatment, beginning most commonly during weeks 2–3 after cessation of HAART. The mean relapse rate constant was 0.45 (0.20 log10 copies) day−1, which was very similar to the mean viral clearance rate constant after drug resumption of 0.35 (0.15 log10 copies) day−1 (P = 0.28). One patient experienced a relapse delay to week 7. All patients except one experienced a relapse burden to >5,000 RNA copies/ml. Ex vivo labeling with BrdUrd showed that CD4 and CD8 cell turnover increased after withdrawal of HAART and correlated with viral load whereas lymphocyte turnover decreased after reinitiation of drug treatment. Virologic relapse occurs rapidly in patients who discontinue suppressive drug therapy, even in patients with a markedly diminished pool of resting, latently infected CD4+ T cells.

Antigen-driven CD4+ T cell and HIV-1 dynamics: Residual viral replication under highly active antiretroviral therapy

Antigen-induced stimulation of the immune system can generate heterogeneity in CD4+ T cell division rates capable of explaining the temporal patterns seen in the decay of HIV-1 plasma RNA levels during highly active antiretroviral therapy. Posttreatment increases in peripheral CD4+ T cell counts are consistent with a mathematical model in which host cell redistribution between lymph nodes and peripheral blood is a function of viral burden. Model fits to patient data suggest that, although therapy reduces HIV replication below replacement levels, substantial residual replication continues. This residual replication has important consequences for long-term therapy and the evolution of drug resistance and represents a challenge for future treatment strategies.

Reduction of HIV-1 in blood and lymph nodes following potent antiretroviral therapy and the virologic correlates of treatment failure

Potent antiretroviral therapy can reduce plasma HIV RNA levels below the threshold of detection for periods of a year or more. The magnitude of HIV RNA reduction in the lymphoid tissue in patients with suppression of HIV RNA levels in plasma beyond 6 months has not been determined. We evaluated levels of HIV RNA and DNA and characterized resistance mutations in blood and inguinal lymph node biopsies obtained from 10 HIV-infected subjects who received 36–52 weeks of indinavir (IDV)/zidovudine (ZDV)/lamivudine (3TC), IDV, or ZDV/3TC. After 1 year of therapy, viral RNA levels in LN of individuals remained detectable but were log10 = 4 lower than in subjects on the triple drug regimen with interruption of therapy or in those treated with ZDV/3TC alone, who had viral loads in their lymph nodes indistinguishable from those expected for untreated patients. In all cases viral DNA remained detectable in lymph nodes and peripheral blood mononuclear cells (PBMC). When plasma virus suppression was incomplete, lymph node and PBMC cultures were positive and drug resistance developed. These studies indicate that pronounced and sustained suppression of plasma viremia by a potent antiretroviral combination is associated with low HIV RNA levels in the lymph nodes 1 year after treatment. Conversely, the persistence of even modest levels of plasma virus after 1 year of treatment reflects ongoing viral replication, the emergence of drug resistance, and the maintenance of high burdens of virus in the lymph nodes.

Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy

The long-term kinetics of T cell production following highly active antiretroviral therapy (HAART) were investigated in blood and lymph node in a group of HIV-infected subjects at early stage of established infection and prospectively studied for 72 wk. Before HAART, CD4 and CD8 T cell turnover was increased. However, the total number of proliferating CD4+ T lymphocytes, i.e., CD4+Ki67+ T lymphocytes, was not significantly different in HIV-infected (n = 73) and HIV-negative (n = 15) subjects, whereas proliferating CD8+Ki67+ T lymphocytes were significantly higher in HIV-infected subjects. After HAART, the total body number of proliferating CD4+Ki67+ T lymphocytes increased over time and was associated with an increase of both naive and memory CD4+ T cells. The maximal increase (2-fold) was observed at week 36, whereas at week 72 the number of proliferating CD4+ T cells dropped to baseline levels, i.e., before HAART. The kinetics of the fraction of proliferating CD4 and CD8 T cells were significantly correlated with the changes in the total body number of these T cell subsets. These results demonstrate a direct relationship between ex vivo measures of T cell production and quantitative changes in total body T lymphocyte populations. This study provides advances in the delineation of the kinetics of T cell production in HIV infection in the presence and/or in the absence of HAART.

Antiretroviral resistance during successful therapy of HIV type 1 infection

HIV type 1 (HIV-1) drug resistance mutations were selected during antiretroviral therapy successfully suppressing plasma HIV-1 RNA to <50 copies/ml. New resistant mutant subpopulations were identified by clonal sequencing analyses of viruses cultured from blood cells. Drug susceptibility tests showed that biological clones of virus with the mutations acquired during successful therapy had increased resistance. Each of the five subjects with new resistant mutants had evidence of some residual virus replication during highly active antiretroviral therapy (HAART), based on transient episodes of plasma HIV-1 RNA > 50 copies/ml and virus env gene sequence changes. Each had received a suboptimal regimen before starting HAART. Antiretroviral-resistant HIV-1 can be selected from residual virus replication during HAART in the absence of sustained rebound of plasma HIV-1 RNA.

Influence of follicular dendritic cells on decay of HIV during antiretroviral therapy

Drug treatment of HIV type 1 (HIV-1) infection leads to a rapid initial decay of plasma virus followed by a slower second phase of decay. To investigate the role of HIV-1 retained on follicular dendritic cells (FDCs) in this process, we have developed and analyzed a mathematical model for HIV-1 dynamics in lymphoid tissue (LT) that includes FDCs. Analysis of clinical data using this model indicates that decay of HIV-1 during therapy may be influenced by release of FDC-associated virus. The biphasic character of viral decay can be explained by reversible multivalent binding of HIV-1 to receptors on FDCs, indicating that the second phase of decay is not necessarily caused by long-lived or latently infected cells. Furthermore, viral clearance and death of short-lived productively infected cells may be faster than previously estimated. The model, with reasonable parameter values, is consistent with kinetic measurements of viral RNA in plasma, viral RNA on FDCs, productively infected cells in LT, and CD4+ T cells in LT during therapy.

Decreased human immunodeficiency virus type 1 plasma viremia during antiretroviral therapy reflects downregulation of viral replication in lymphoid tissue.

Although several immunologic and virologic markers measured in peripheral blood are useful for predicting accelerated progression of human immunodeficiency virus (HIV) disease, their validity for evaluating the response to antiretroviral therapy and their ability to accurately reflect changes in lymphoid organs remain unclear. In the present study, changes in certain virologic markers have been analyzed in peripheral blood and lymphoid tissue during antiretroviral therapy. Sixteen HIV-infected individuals who were receiving antiretroviral therapy with zidovudine for > or = 6 months were randomly assigned either to continue on zidovudine alone or to add didanosine for 8 weeks. Lymph node biopsies were performed at baseline and after 8 weeks. Viral burden (i.e., HIV DNA copies per 10(6) mononuclear cells) and virus replication in mononuclear cells isolated from peripheral blood and lymph node and plasma viremia were determined by semiquantitative polymerase chain reaction assays. Virologic and immunologic markers remained unchanged in peripheral blood and lymph node of patients who continued on zidovudine alone. In contrast, a decrease in virus replication in lymph nodes was observed in four of six patients who added didanosine to their regimen, and this was associated with a decrease in plasma viremia. These results indicate that decreases in plasma viremia detected during antiretroviral therapy reflect downregulation of virus replication in lymphoid tissue.

Terapêutica antiretroviral e metabolismo lipídico

Dissertação para obtenção do grau de Mestre no Instituto Superior de Ciências da Saúde Egas Moniz

Immune recovery in HIV-infected patients after candida esophagitis is impaired despite long-term antiretroviral therapy.

OBJECTIVE Candida esophagitis belongs to the most common AIDS-defining diseases, however, a comprehensive immune pathogenic concept is lacking. DESIGN We investigated the immune status of 37 HIV-1-infected patients from the Swiss HIV cohort study at diagnosis of Candida esophagitis, 1 year before, 1 year later and after 2 years of suppressed HIV RNA. We compared these patients to 3 groups: 37 HIV-1-infected patients without Candida esophagitis but similar CD4 counts as the patients at diagnosis (advanced HIV group), 15 HIV-1-infected patients with CD4 counts >500 cells/μl, CD4 nadir >350 cells/μl and suppressed HIV RNA under combination antiretroviral therapy (cART) (early cART group), and 20 healthy individuals. METHODS We investigated phenotype, cytokine production and proliferative capacity of different immune cells by flow cytometry and ELISpot. RESULTS We found that patients with Candida esophagitis had nearly abolished CD4 proliferation in response to C. albicans, significantly increased percentages of dysfunctional CD4 cells, significantly decreased cytotoxic NK-cell counts and peripheral innate lymphoid cells and significantly reduced IFN-γ and IL-17 production compared to the early cART group and healthy individuals. Most of these defects remained for more than 2 years despite viral suppression. The advanced HIV group without opportunistic infection showed partly improved immune recovery. CONCLUSIONS Our data indicate that Candida esophagitis in HIV-1-infected patients is caused by an accumulation of multiple, partly Candida-specific immunological defects. Long-term immune recovery is impaired, illustrating that specific immunological gaps persist despite cART. These data also support the rationale for early cART initiation to prevent irreversible immune defects.

Effect of Depression and Substance Abuse on Antiretroviral Therapy (ART) Adherence in Men Who Have Sex With Men (MSM) of Mexican Descent on the US-Mexico Border

Thesis (Master's)--University of Washington, 2016-06

Antiretroviral Treatment as Prevention in African HIV-1 Serodiscordant Couples: Understanding the Challenges and Opportunities

Thesis (Ph.D.)--University of Washington, 2016-06

Systemic monocyte activation levels and developmental milestone attainment in HIV-infected infants initiating antiretroviral therapy

Thesis (Master's)--University of Washington, 2016-06

Will diverse Tat interactions lead to novel antiretroviral drug targets?

More than fifteen years following the description of Tat as a critical HIV gene expression regulatory protein, additional roles for Tat in HIV replication have been described, including reverse transcription. Tat achieves function through direct interaction with viral proteins, including reverse transcriptase, and numerous cellular proteins including cyclin T1, RNA polymerase 11, protein kinase R (PKR), p300/CBP, and P/CAF. Despite our advanced knowledge of how Tat operates, this has not yet resulted in the discovery of effective agents capable of targeting various Tat functions. Nevertheless, Tat remains an attractive, virus-specific molecule and detailed understanding of specific protein interaction holds promise for future drug discovery.

Increased health care utilization and increased antiretroviral use in HIV-infected individuals with mental health disorders

Objectives The aims of the study were to describe the prevalence and associations of mental health disorder (MHD) among a cohort of HIV-infected patients attending the Victorian HIV/AIDS Service between 1984 and 2000, and to examine whether antiretroviral therapy use or mortality was influenced by MHD (defined as a record of service provision by psychiatric services on the Victorian Psychiatric Case Register). It was hypothesized that HIV-positive individuals with MHD would have poorer treatment outcomes, reduced responses to highly active antiretroviral therapy (HAART) and increased mortality compared with those without MHD. Methods This is a retrospective cohort of 2981 individuals (73% of the Victorian population diagnosed with HIV infection) captured on an HIV database which was electronically matched with the public Victorian Psychiatric Case Register (VPCR) (accounting for 95% of public system psychiatry service provision). The prevalence, dates and recorded specifics of mental health disorders at the time of the electronic match on 1 June 2000 are described. The association with recorded MHD, gender, age, AIDS illness, HIV exposure category, duration and type of antiviral therapy, treatment era (prior to 1986, post-1987 and pre-HAART, and post-HAART) on hospitalization and mortality at 1 September 2001 was assessed. Results Five hundred and twenty-five individuals (17.6% of the Victorian HIV-positive population) were recorded with MHD, most frequently coded as attributable to substance dependence/abuse or affective disorder. MHD was diagnosed prior to HIV in 33% and, of those diagnosed after HIV, 93.8% were recorded more than 1 year after the HIV diagnosis. Schizophrenia was recorded in 6% of the population with MHD. Hospitalizations for both psychiatric and nonpsychiatric illness were more frequent in those with MHD (relative risk 5.4; 95% confidence interval 3.7, 8.2). The total number of antiretrovirals used (median 6.4 agents vs 5.5 agents) was greater in those with MHD. When adjusted for antiretroviral treatment era, HIV exposure category, CD4 cell count and antiretroviral therapy, survival was not affected by MHD. Conclusions MHD is frequent in this population with HIV infection and is associated with increased healthcare utilization but not with reduced survival.