T cell-tropic HIV efficiently infects alveolar macrophages through contact with infected CD4+ T cells

Abstract

Alveolar macrophages (AMs) are critical for defense against airborne pathogens and AM dysfunction is thought to contribute to the increased burden of pulmonary infections observed in individuals living with HIV-1 (HIV). While HIV nucleic acids have been detected in AMs early in infection, circulating HIV during acute and chronic infection is usually CCR5 T cell-tropic (T-tropic) and enters macrophages inefficiently in vitro. The mechanism by which T-tropic viruses infect AMs remains unknown. We collected AMs by bronchoscopy performed in HIV-infected, antiretroviral therapy (ART)-naive and uninfected subjects. We found that viral constructs made with primary HIV envelope sequences isolated from both AMs and plasma were T-tropic and inefficiently infected macrophages. However, these isolates productively infected macrophages when co-cultured with HIV-infected CD4+ T cells. In addition, we provide evidence that T-tropic HIV is transmitted from infected CD4+ T cells to the AM cytosol. We conclude that AM-derived HIV isolates are T-tropic and can enter macrophages through contact with an infected CD4+ T cell, which results in productive infection of AMs. CD4+ T cell-dependent entry of HIV into AMs helps explain the presence of HIV in AMs despite inefficient cell-free infection, and may contribute to AM dysfunction in people living with HIV.

Unlocking the complexity of HIV and Mycobacterium tuberculosis coinfection

“…In the nonhuman primate model of SIV infection, an initial heightened inflammatory response in AMs following systemic SIV infection transitioned to a blunted response phenotype during chronic infection (6). This transition is thought to reflect the environment associated with HIV infection and not the direct infection of AMs, as although AMs can support HIV infection (7), it occurs in only a minority of AMs in the lungs of PLWH. Despite low amounts of infected AMs, those collected from the lungs of PLWH not on ART showed reduced induction of apoptosis after in vitro infection with M. tuberculosis that was linked to higher expression of IL-10 and suppression of the TNF-α response (8).…”

Pulmonary Immune Dysregulation and Viral Persistence During HIV Infection

“…Most acute HIV-1 infections are caused by the CCR5-tropic strain (T-tropic strain), which preferentially targets T-cells. Although it’s not very efficient at infecting macrophages on its own, its infectivity is enhanced significantly during cell-to-cell contact between AMs and infected CD4 T-cells, as has been recently shown by Schiff and his group, suggesting that AM HIV entry during acute infection is CD4 T-cell dependent ( 53 ). Within the AM cell pool (CD206+) two subsets have been identified based on size (FSC) and granularity (SSC) – small and large AMs ( 56 ).…”

“…Upon reaching the lung, HIV is seeded into multiple cell types: CD4 T-cells, DN T-cells, and AMs. Although HIV preferentially infects CD4 T-cells, which account for ~6% of total BAL cells in healthy non-smokers, AMs, which account for ~85% of total BAL cells, are also infected (27,(51)(52)(53). Although data on pulmonary immune perturbations during primary acute HIV infection is scarce, in vitro experiments on human lung lymphocytes and in vivo animal SIV models suggest that during the acute phase of infection pulmonary interstitial CD4 T-cells are more severely and rapidly depleted compared to the blood compartment that is largely due to CCR5+ memory CD4 T-cells' high susceptibility to CCR5-topic HIV-1 infection, which make up the vast majority of the lung CD4 T-cell pool (54,55).…”

Host Immune-Metabolic Adaptations Upon Mycobacterial Infections and Associated Co-Morbidities

“…TNF secretion was reduced in HIV/M.tb co-infected macrophages compared to M.tb alone in a THP-1 cell model and human AMs (161,162), as well as TNFdependent apoptosis (161)(162)(163). There is evidence of HIV capacity to infect AMs (164,165) which can act as viral reservoirs (166). HIV-infected AMs present impaired phagocytic function (167), and HIV inhibits phagocytosis in hMDMs in a Nef-dependent manner (168).…”