Differences in APOBEC3G Expression in CD4+ T Helper Lymphocyte Subtypes Modulate HIV-1 Infectivity

The cytidine deaminases APOBEC3G and APOBEC3F exert anti–HIV-1 activity that is countered by the HIV-1 vif protein. Based on potential transcription factor binding sites in their putative promoters, we hypothesized that expression of APOBEC3G and APOBEC3F would vary with T helper lymphocyte differentiation. Naive CD4+ T lymphocytes were differentiated to T helper type 1 (Th1) and 2 (Th2) effector cells by expression of transcription factors Tbet and GATA3, respectively, as well as by cytokine polarization. APOBEC3G and APOBEC3F RNA levels, and APOBEC3G protein levels, were higher in Th1 than in Th2 cells. T cell receptor stimulation further increased APOBEC3G and APOBEC3F expression in Tbet- and control-transduced, but not in GATA3-transduced, cells. Neutralizing anti–interferon-γ antibodies reduced both basal and T cell receptor-stimulated APOBEC3G and APOBEC3F expression in Tbet- and control-transduced cells. HIV-1 produced from Th1 cells had more virion APOBEC3G, and decreased infectivity, compared to virions produced from Th2 cells. These differences between Th1- and Th2-produced virions were greater for viruses lacking functional vif, but also seen with vif-positive viruses. Over-expression of APOBEC3G in Th2 cells decreased the infectivity of virions produced from Th2 cells, and reduction of APOBEC3G in Th1 cells increased infectivity of virions produced from Th1 cells, consistent with a causal role for APOBEC3G in the infectivity difference. These results indicate that APOBEC3G and APOBEC3F levels vary physiologically during CD4+ T lymphocyte differentiation, that interferon-γ contributes to this modulation, and that this physiological regulation can cause changes in infectivity of progeny virions, even in the presence of HIV-1 vif

Pre‐existing Minority Drug‐Resistant HIV‐1 Variants, Adherence, and Risk of Antiretroviral Treatment Failure

The clinical relevance of detecting minority drug-resistant HIV-1 variants is uncertain

Comparison of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection

BACKGROUND The optimal sequencing ofantiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies. METHODS This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure ofthe second three-drug regimen. RESULTS A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2. 3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure ofthe second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure ofthe second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure ofthe first regimen (hazard ratio, 0.39) and the firstvirologic failure (hazard ratio, 0.34). Starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the firstvirologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure ofthe first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression. CONCLUSIONS The efficacy ofantiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study

Management of antiretroviral therapy for HIV infection : analyzing when to change therapy

HD28 .M414 no.4043-98,

Traumatic events and mental health: The amplifying effects of pre-trauma systemic inflammation

•Experiments have shown that inflammation can amplify the aversiveness of threats.•We hypothesized that inflammation amplifies the impact of trauma on mental health.•We tested this hypothesis in a longitudinal study of sexual and gender minority youth.•Pre-trauma inflammation amplified the effects of trauma on subsequent mental health.•Studies on the interaction of inflammation and trauma may lead to new interventions. Traumatic experiences are strongly predictive of adverse mental health outcomes. Experimental studies have demonstrated that systemic inflammation can increase reactivity to threatening stimuli. It is not known whether naturally occurring inflammation amplifies the impact of traumatic experiences on mental health. Here we test whether incident traumatic events are more predictive of adverse mental health outcomes for individuals with greater pre-trauma systemic inflammation in a racially and ethnically diverse cohort study of youth assigned male at birth who identify as sexual or gender minorities (ages 16–29, n = 518), a group at high risk for trauma exposure. Measures of inflammation, depression symptom severity, and perceived stress were measured at baseline. One year later, depression symptom severity and perceived stress were measured again, and participants reported the traumatic events they had experienced in the intervening year. In a model adjusted for baseline depression symptom severity and other key covariates, we found that higher baseline levels of interleukin-1β amplified the effect of incident trauma exposure on depression symptom severity at follow-up (β = 0.234, SE = 0.080, P = 0.004). In a model adjusted for baseline perceived stress and other key covariates, we found that higher baseline scores on a multi-marker inflammatory index amplified the effect of incident trauma exposure on perceived stress at follow-up (β = 0.243, SE = 0.083, P = 0.003). These findings suggest that greater pre-trauma inflammation may predict poorer mental health following trauma exposure. Understanding how inflammation interacts with trauma to shape mental health may generate novel insights for preventing and treating the debilitating psychological consequences of trauma

Lower HIV Provirus Levels Are Associated with More APOBEC3G Protein in Blood Resting Memory CD4+ T Lymphocytes of Controllers <i>In Vivo</i>

<div><p>Immunodeficiency does not progress for prolonged periods in some HLA B57- and/or B27-positive subjects with human immunodeficiency virus type 1 (HIV) infection, even in the absence of antiretroviral therapy (ART). These “controllers” have fewer HIV provirus-containing peripheral blood mononuclear cells than “non-controller” subjects, but lymphocytes that harbor latent proviruses were not specifically examined in studies to date. Provirus levels in resting memory cells that can serve as latent reservoirs of HIV in blood were compared here between controllers and ART-suppressed non-controllers. APOBEC3G (A3G), a cellular factor that blocks provirus formation at multiple steps if not antagonized by HIV virion infectivity factor (Vif), was also studied. HLA-linked HIV control was associated with less provirus and more A3G protein in resting CD4+ T central memory (Tcm) and effector memory (Tem) lymphocytes (provirus: p = 0.01 for Tcm and p = 0.02 for Tem; A3G: p = 0.02 for Tcm and p = 0.02 for Tem). Resting memory T cells with the highest A3G protein levels (>0.5 RLU per unit of actin) had the lowest levels of provirus (<1,000 copies of DNA per million cells) <i>in vivo</i> (p = 0.03, Fisher's exact test). Using two different experimental approaches, Vif-positive viruses with more A3G were found to have decreased virion infectivity <i>ex vivo</i>. These results raise the hypothesis that HIV control is associated with increased cellular A3G that may be packaged into Vif-positive virions to add that mode of inhibition of provirus formation to previously described adaptive immune mechanisms for HIV control.</p></div

Virion-packaged A3G and infectivity of endogenous viruses produced from activated CD4+ T lymphocytes <i>ex vivo</i>.

<p>(<b>A</b>) Increased virion-packaged A3G protein was associated with decreased infectivity of endogenous viruses produced from activated CD4+ T lymphocytes. Virions released from activated CD4+ T lymphocytes of ART-suppressed (AS) non-controller subjects were analyzed for infectivity using the TZM-bl assay and for virion-associated A3G protein by in-virion Western blotting. CD4+ T lymphocytes were sorted for positivity for CD25, CD69, CD38 and HLA-DR from blood of 5 of the AS non-controller subjects. Activation was maintained in <i>ex vivo</i> cultures by anti-CD3/CD28 antibody coated beads. HIV-1 p24 antigen measurement monitored production of endogenous Vif-positive HIV-1 <i>ex vivo</i>. Virion content was normalized by p24 antigen amount for both infectivity and virion A3G protein measurements. Bars represent mean +/− standard deviation (SD). (<b>B</b>) Virion infectivity was significantly inversely correlated with amount of A3G protein in virions. P value was determined by Spearman correlation.</p

Higher cellular A3G protein levels were associated with decreased infectivity and spread of HIV virions after <i>ex vivo</i> activation and infection of primary memory T lymphocytes.

<p>(<b>A</b>) Blood resting CD4+ T central memory (Tcm) and effector memory (Tem) cells sorted from the same uninfected subject were activated and then infected <i>ex vivo</i> with a Vif-positive, CCR5-tropic clinical isolate of HIV. HIV p24 antigen was monitored over time in supernatant fluids from separate Tcm and Tem cell cultures. Virus spread through the culture of Tcm cells more rapidly than it did through the culture of Tem cells previously shown to have higher A3G protein levels (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076002#pone-0076002-g002" target="_blank">Figure 2</a>). (<b>B</b>) Infectivity of virions produced from Tcm cells was greater than that of virions produced from Tem cells. Infectivity was quantified by luciferase activity normalized by amount of p24 antigen added to TZM-bl reporter cells. Bars represent mean +/− standard deviation (SD).</p