HIV-1–Infected Peripheral Blood Mononuclear Cells Enhance Neutrophil Survival and HLA-DR Expression Via Increased Production of GM-CSF: Implications for HIV-1 Infection

Abstract

Objective HIV-1 bound to intact neutrophils efficiently infects activated peripheral blood mononuclear cells (PBMC). Here, we evaluated the effect of the local milieu created by activated PBMC before and after HIV-1 infection on neutrophil survival and HLA-DR expression, with emphasis placed on a role for GM-CSF. Methods PBMC of healthy adult individuals were activated by phytohemagglutinin (PHA) or anti-CD3/anti-CD28 and were subsequently cultured without (HIV-1−) or with HIV-1 (HIV-1+). The effects of the culture supernatants or recombinant GM-CSF on survival and HLA-DR expression by neutrophils of healthy adult individuals and of HIV-1-infected individuals were evaluated using flow cytometry. Results Conditioned medium from PHA-activated PBMC (HIV-1− and HIV-1+) increased neutrophil survival and induced HLA-DR expression by neutrophils of healthy individuals in a GM-CSF dependent fashion. HIV-1 infection variably, but consistently, increased GM-CSF production by PHA-activated PBMC but not GM-CSF production by anti-CD3/anti-CD28-activated PBMC. The latter was correlated with a loss of CD3+GM-CSF+ cells after infection. Neutrophils of elite controllers exhibited a diminished HLA-DR response to GM-CSF in culture, whereas neutrophils of HIV-1+ subjects having a low viral load on anti-retroviral therapy or subjects with a high viral load exhibited a range of HLA-DR responses. Conclusions GM-CSF production within the mucosa or draining lymph nodes may promote HIV-1 infection by facilitating sustained contact between viable neutrophils with bound HIV-1 and CD4 lymphocytes. The minimal effect of GM-CSF on HLA-DR expression by neutrophils of elite controllers provides indirect support for this conclusion.

Learning to Be Elite: Lessons From HIV-1 Controllers and Animal Models on Trained Innate Immunity and Virus Suppression

“…As anticipated, EC granulocytes exhibited elevated expression of antiviral factors when stimulated with HIV-1 ( 40 ). Neutrophils from ECs also demonstrated a better survival than those from non-controllers when cultured with GM-CSF secreted from HIV-1-infected PBMCs ( 49 ), but their antibody-dependent phagocytosis was not different from that in HIV-1 non-controllers ( 33 ). Though their intrinsic immune functions may not be upregulated in ECs, several studies indicate the potential alteration of other immune cells by neutrophils.…”

Interactions between Human Immunodeficiency Virus Type 1 and Polymorphonuclear Neutrophils

“…Furthermore, HIV binding to PMN is enhanced by inflammatory stimuli produced by T lymphocytes, such as TNF-α, in turn increasing the rate of PBMC infection [16]. Interestingly, sustained contact between viable HIV-1-bearing PMN and CD4 lymphocytes may be facilitated through GM-CSF production by HIV-1-infected PBMC, thus prolonging PMN survival and increasing the percentage of HLA-DR+ PMN [43]. PMN are abundant in the inflamed oral and genital mucosae and have also been observed in draining lymph nodes of HIV-1-infected patients [44].…”

Synthetic Mucin Gels with Self‐Healing Properties Augment Lubricity and Inhibit HIV‐1 and HSV‐2 Transmission

“…HIV‐1 capsid protein p24 was expressed in large in during the early stages of HIV‐1 infection. [ 84 ] Thus, the p24 expression in HIV‐1‐infected hPBMCs was studied by quantifying p24 in cell lysates using an ELISA plate (p24 ELISA, Cat. No.…”