Complex Interactions Between Human Immunodeficiency Virus Type-1, Sex, and Osteopontin Influence Viral Replication and Leukocyte Proportions in Tissues

Farina J Mahmud,Thomas Boucher,Bess Carlson,Elizabeth Greif,Claire Lyons,Kelly A Metcalf Pate,Amanda M Brown

doi:10.3389/fviro.2021.690360

Farina J Mahmud, Thomas Boucher + Show 5 more

Open Access

https://doi.org/10.3389/fviro.2021.690360

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Abstract

Evidence suggesting that HIV pathogenesis differs by sex, a variable known to influence the extent and breadth of immune responses in health and disease continues to accumulate. Host factors that promote or inhibit HIV replication may do so in a way that varies by sex. Prior studies using cultured human macrophages demonstrated that osteopontin (OPN)/secreted phosphoprotein-1 (SPP1) stimulates HIV replication. To test whether OPN has the same positive impact on virus replication at the level of tissues, we used a humanized mice model of low-level chronic HIV infection and in which OPN RNA and protein expression was inhibited with targeted aptamers. Interestingly, 4 months after infection when there were no significant differences in HIV viral load in plasma between groups however in contrast, in the spleen, lung, and liver the tissue burden of HIV RNA, as well as the proportion of leukocytes in female and male mice differed depending on whether OPN was expressed or not. The findings collectively demonstrate the potential for complex interactions between host factors like OPN and sex to influence different facets of HIV tissue-level pathogenesis.

Highlights

Human immunodeficiency virus type 1 (HIV-1) infection is managed with antiretroviral (ART) therapy while research toward a cure continues
For female HIV-infected mice irrespective of OPN levels, while a positive trend in the relationship between the percentage of human CD45 (hCD45)+ cells at initial infection and viral load at the study endpoint was observed [Figure 1B, Spearman coefficients], the correlations were not significant (Figure 1B, NS). These results suggest that the overall number of hCD45+ cells at the time of engraftment did not drive plasma HIV copy number at the study endpoint
It is important here to highlight that the relationship between hCD45+ cells and viral copy number is expected to be influenced by the genetic background and susceptibility of the three human donors used for humanization [32, 33]

Summary

Introduction

Human immunodeficiency virus type 1 (HIV-1) infection is managed with antiretroviral (ART) therapy while research toward a cure continues. HIV-1 disseminates rapidly into tissues forming sanctuaries and reservoirs which are harder to target [1,2,3]. Replication-competent virus in such tissue reservoirs in tissues rebound into a full-fledged infection if ART is interrupted [4, 5]. One of the significant challenges in HIV eradication strategies has been the absolute suppression of replication from tissue reservoirs [1, 4]. Identifying and increasing our understanding of host cell genes that promote HIV replication in tissues would provide critical new knowledge. Immune cells’ ability to circulate and surveil tissues is potentially hijacked by HIV-1 to facilitate the formation of sanctuaries and reservoirs, suggesting a complex interaction between viral and host factors [6]. Different anatomical and physiological properties of tissues contribute to

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