Hyaluronic acid is a negative regulator of mucosal fibroblast-mediated enhancement of HIV infection

Abstract

The majority of HIV infections are established through the genital or rectal mucosa. Fibroblasts are abundant in these tissues, and although not susceptible to infection, can potently enhance HIV infection of CD4+ T cells. Hyaluronic acid (HA) is a major component of the extracellular matrix of fibroblasts, and its levels are influenced by the inflammatory state of the tissue. Since inflammation is known to facilitate HIV sexual transmission, we investigated the role of HA in genital mucosal fibroblast-mediated enhancement of HIV infection. Depletion of HA by CRISPR-Cas9 in primary foreskin fibroblasts augmented the ability of the fibroblasts to increase HIV infection of CD4+ T cells. This amplified enhancement required direct contact between the fibroblasts and CD4+ T cells, and could be attributed to both increased rates of trans-infection and the increased ability of HA-deficient fibroblasts to push CD4+ T cells into a state of higher permissivity to infection. This HIV-permissive state was characterized by differential expression of genes associated with regulation of cell metabolism and death. Our results suggest that conditions resulting in diminished cell-surface HA on fibroblasts, such as genital inflammation, can promote HIV transmission by conditioning CD4+ T cells toward a state more vulnerable to infection by HIV.

Roles of Virion-Incorporated CD162 (PSGL-1), CD43, and CD44 in HIV-1 Infection of T Cells

“…In this process, virion-incorporated CD44 and HA bound to CD44 are unlikely to contribute to virus capture because mucosal fibroblasts capture HIV-1 even when HIV-1 is produced from 293T cells that do not express CD44. Furthermore, the knockout of HA synthase 2 in mucosal fibroblasts does not affect virus capture efficiency [100], suggesting that HA on the surface of mucosal fibroblasts does not play a major role in trans-infection. Therefore, the molecular mechanisms of mucosal fibroblast-and FRC-mediated trans-infection are distinct.…”

“…In addition to FRCs, mucosal fibroblasts also mediate trans-infection [99,100]. In this process, virion-incorporated CD44 and HA bound to CD44 are unlikely to contribute to virus capture because mucosal fibroblasts capture HIV-1 even when HIV-1 is produced from 293T cells that do not express CD44.…”

Advances in HIV Eradication Strategies

“…It has also been shown that CRISPR/Cas9 technology can increase the function of HIV-infected CD4 + T cells after removing hyaluronic acid from fibroblasts. Hyaluronic acid is the main component of the fibroblast extracellular matrix, and its level is affected by tissue inflammation 55 . The three successfully cured HIV cases suggest that anti-HIV gene therapy based on hematopoietic stem cells (HPSC) can theoretically cure HIV infection.…”

Myrtle-Functionalized Nanofibers Modulate Vaginal Cell Population Behavior While Counteracting Microbial Proliferation

“…The vaginal mucosa is a squamous epithelium organized in different levels where cells become more differentiated, migrating apically [1]. Here, resident fibroblasts are responsible for the production of hyaluronic acid, thus maintaining hydration of the area [2].…”