Interleukin‐4 Up‐Regulates T‐Tropic Human Immunodeficiency Virus Type 1 Transcription in Primary CD4⁺ CD38⁺ T‐Lymphocyte Subset

Abstract

The capacity of human immunodeficiency virus type 1 (HIV‐1) to infect resting cells and to produce progeny particles may contribute significantly to its pathogenicity in vivo. We previously reported that primary culture of resting CD4+ CD38+ T‐lymphocyte subset had higher production rate of CXCR4‐using (X4) HIV‐1 than CD4+ CD38− subset. Interleukin (IL)‐4 highly contributed to the up‐regulation of the X4 virus production in the CD38+ subset. Here, we show evidences that IL‐4 treatment of both resting CD38+ and CD38− subsets allowed the adsorption, entry, and integration of X4 virus at similar rates, while the following viral transcription rate was significantly lower in the CD38− than CD38+ subset. Treatment of the CD38 subsets with IL‐4 or phytohemagglutinin revealed no association of X4 virus replication ability in the subsets with classic T‐cell activation or proliferation. Interestingly, the activator protein (AP)‐1 was significantly activated in the CD38+ subset after IL‐4 treatment, while both nuclear factor (NF)‐κB and signal transducers and activator of transcription (STAT)‐6 were activated in the IL‐4‐treated CD38+ and CD38− subsets at similar levels. Thus, IL‐4‐dependent X4 HIV‐1 transcription occurs efficiently in the CD38+ but not CD38− subset of CD4+ population and AP‐1 could play a significant role on viral transcription, leading to the up‐regulated X4 virus production in the CD38+ subset.

Endogenous factors enhance HIV infection of tissue naive CD4 T cells by stimulating high molecular mass APOBEC3G complex formation

“…To identify the factors present in conditioned medium necessary to render tissue-derived naive CD4 T cells permissive, we considered the study by Unutmaz et al ( 18 ), which showed that 10–20 ng/ml IL-2, -4, -7, or -15 rendered otherwise unstimulated blood-derived CD4 T cells susceptible to HIV infection. Consistent with this and other studies ( 19 , 20 ), we found that addition of 20 ng/ml IL-2, -4, -7, or -15 was sufficient for tissue-derived naive CD4 T cells to sustain a spreading infection (unpublished data).…”

An HIV-1 Replication Pathway Utilizing Reverse Transcription Products That Fail To Integrate

“…In our preliminary testing, we confirmed the findings presented in prior reports (49,50,81,83) that exposure of resting peripheral blood CD4 ϩ T cells to IL-2, IL-4, IL-7, or IL-15 enhances infection without inducing T cell activation. Prior studies have demonstrated that cytokines have multiple influences on resting T cells that increase the permissiveness of these cells to HIV-1 replication.…”

“…S5 in the supplemental material), the viruses expressed HIV-1 envelope protein from the native virally encoded env gene. ϩ resting T cells (82,83), and in tonsils, IL-4 has been shown to increase the permissiveness of resident CD4…”

Distinct cytokine and regulatory T cell profile at pleural sites of dual HIV/tuberculosis infection compared to that in the systemic circulation

“…In turn, TNF‐α supports IFN‐γ expression and may promote CD4 depletion [10]. A role for Th2 cytokines on HIV‐1 activity is more controversial [11,12]. Transforming growth factor (TGF)‐β, a prominent anti‐inflammatory cytokine is abundant during TB and may promote viral activity by counteraction to anti‐HIV‐1 immune responses either directly or through support of expansion of regulatory T cells (T reg ) [13,14].…”