Mathematical analysis of a class of HIV infection models of CD4+ T-cells with combined antiretroviral therapy

Abstract Background. Persistent human immunodeficiency virus (HIV) within the CD4+ T-cell reservoir is an obstacle to eradication. We hypothesized that adding raltegravir and maraviroc to standard combination antiretroviral therapy (cART) during early HIV infection could substantially reduce viral reservoirs as a step towards eradication. Methods. A prospective, randomized, double-blinded, placebo-controlled pilot trial enrolled 32 participants with documented early (<6 months) HIV infection to either standard cART (emtricitabine/tenofovir/lopinavir/ritonavir) or intensive cART (standard regimen + raltegravir/maraviroc). Human immunodeficiency virus reservoirs were assessed at baseline and at 48 weeks by (1) proviral DNA, (2) cell-associated RNA, and (3) replication-competent virus, all from purified blood CD4+ T cells, and (4) gut proviral DNA. A multiassay algorithm (MAA) on baseline sera estimated timing of infection. Results. Thirty individuals completed the study to the 48-week endpoint. The reduction in blood proviral burden was −1.03 log DNA copies/106 CD4+ T cells versus −.84 log in the standard and intensive groups, respectively (P = .056). Overall, there was no significant difference in the rate of decline of HIV-associated RNA, replication-competent virus in blood CD4+ T cells, nor proviral gut HIV DNA to 48 weeks. Individuals who presented with more recent HIV infection had significantly lower virus reservoirs, and cART tended to reduce their reservoirs to a greater extent. Conclusions. Intensive cART led to no additional reduction in the blood virus reservoir at 48 weeks compared with standard cART. Human immunodeficiency virus reservoir size is smaller earlier in HIV infection. Other novel treatment strategies in combination with early cART will be needed to eliminate the HIV latent reservoir.

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Impact of Biological Sex on Immune Activation and Frequency of the Latent HIV Reservoir During Suppressive Antiretroviral Therapy

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa298 ◽

2020 ◽

Vol 222 (11) ◽

pp. 1843-1852 ◽

Cited By ~ 3

Author(s):

Shane D Falcinelli ◽

Bonnie E Shook-Sa ◽

Morgan G Dewey ◽

Sumati Sridhar ◽

Jenna Read ◽

...

Keyword(s):

T Cells ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Immune Activation ◽

Cd4 T Cells ◽

Acute Infection ◽

Interferon Response ◽

Suppressive Therapy ◽

Hiv Reservoir ◽

Latent Hiv

Abstract Background Persistent HIV infection of long-lived resting CD4 T cells, despite antiretroviral therapy (ART), remains a barrier to HIV cure. Women have a more robust type 1 interferon response during HIV infection relative to men, contributing to lower initial plasma viremia. As lower viremia during acute infection is associated with reduced frequency of latent HIV infection, we hypothesized that women on ART would have a lower frequency of latent HIV compared to men. Methods ART-suppressed, HIV seropositive women (n = 22) were matched 1:1 to 22 of 39 ART-suppressed men. We also compared the 22 women to all 39 men, adjusting for age and race as covariates. We measured the frequency of latent HIV using the quantitative viral outgrowth assay, the intact proviral DNA assay, and total HIV gag DNA. We also performed activation/exhaustion immunophenotyping on peripheral blood mononuclear cells and quantified interferon-stimulated gene (ISG) expression in CD4 T cells. Results We did not observe evident sex differences in the frequency of persistent HIV in resting CD4 T cells. Immunophenotyping and CD4 T-cell ISG expression analysis revealed marginal differences across the sexes. Conclusions Differences in HIV reservoir frequency and immune activation appear to be small across sexes during long-term suppressive therapy.

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Effects of HCV co-infection on apoptosis of CD4+ T-cells in HIV-positive patients

Clinical Science ◽

10.1042/cs20080532 ◽

2009 ◽

Vol 116 (12) ◽

pp. 861-870 ◽

Cited By ~ 29

Author(s):

Christian Körner ◽

Benjamin Krämer ◽

Daniela Schulte ◽

Martin Coenen ◽

Stefan Mauss ◽

...

Keyword(s):

T Cells ◽

Hepatitis C ◽

T Cell ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Cell Apoptosis ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Hiv Positive ◽

T Cell Apoptosis

Apoptosis importantly contributes to loss of CD4+ T-cells in HIV infection, and modification of their apoptosis may explain why HIV/HCV (hepatitis C virus)-co-infected patients are more likely to die from liver-related causes, although the effects of HCV on HIV infection remain unclear. In the present study, we studied in a cross-sectional and serial analysis spontaneous ex vivo CD4+ T-cell apoptosis in HIV/HCV-co-infected and HIV-mono-infected patients before and after HAART (highly active antiretroviral therapy). Apoptosis of peripheral blood CD4+ T-cells was measured by both a PARP [poly(ADP-ribose) polymerase] and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay to detect cells with irreversible apoptosis. Although hepatitis C alone did not increase CD4+ T-cell apoptosis, HCV co-infection disproportionately increased elevated rates of apoptosis in CD4+ T-cells from untreated HIV-positive patients. Increased CD4+ T-cell apoptosis was closely correlated with HIV, but not HCV, viral loads. Under HAART, increased rates of CD4+ T-cell apoptosis rapidly decreased both in HIV-mono-infected and HIV/HCV-co-infected patients, without any significant difference in apoptosis rates between the two patient groups after 4 weeks of therapy. Nevertheless residual CD4+ T-cell apoptosis did not reach the normal levels seen in healthy controls and remained higher in HIV patients receiving protease inhibitors than in patients with other antiretroviral regimens. The results of the present study suggest that HCV co-infection sensitizes CD4+ T-cells towards apoptosis in untreated HIV-positive patients. However, this effect is rapidly lost under effective antiretroviral therapy.

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