Comprehensive Assessment of HIV Target Cells in the Distal Human Gut Suggests Increasing HIV Susceptibility Toward the Anus

Abstract

Background Prevention of rectal HIV transmission is a high priority goal for vaccines and topical microbicides because a large fraction of HIV transmissions occurs rectally. Yet, little is known about the specific target cell milieu in the human rectum other than inferences made from the colon. Methods We conducted a comprehensive comparative in situ fluorescence study of HIV target cells (CCR5-expressing T cells, macrophages and putative dendritic cells) at 4 and 30 cm proximal of the anal canal in 29 healthy individuals, using computerized analysis of digitized combination stains. Results Most strikingly, we find that more than three times as many CD68+ macrophages express the HIV co-receptor CCR5 in the rectum than the colon (p=0.0001), and as such rectal macrophages appear biologically closer to the HIV-susceptible CCR5high phenotype in the vagina than the mostly HIV-resistant CCR5low phenotype in the colon. Putative CD209+ dendritic cells are generally enriched in the colon compared to the rectum (p=0.0004), though their CCR5 expression levels are similar in both compartments. CD3+ T cell densities and CCR5 expression levels are comparable in the colon and rectum. Conclusions Our study establishes the target cell environment for HIV infection in the human distal gut and demonstrates in general terms that the colon and rectum are immunologically distinct anatomical compartments. Greater expression of CCR5 on rectal macrophages suggests that the most distal sections of the gut may be especially vulnerable to HIV infection. Our findings also emphasize that caution should be exercised when extrapolating data obtained from colon tissues to the rectum.

Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection

“…We extended our investigations to a high-dose rectal challenge model as vaginal and rectal mucosae are anatomically and immunologically distinct compartments (Mcelrath et al, 2013, Mitchell et al, 2014, Cheeseman et al, 2016a, Sips et al, 2016), and the estimated risk of receptive anal intercourse is greater than that for receptive vaginal intercourse (Patel et al, 2014). Also, because neither the GalCer-blocking CH38 IgA2 nor ADCC-mediating CH54 IgG capture infectious virions, their greatest activity may be against cell-associated Env and better assessed in an in vivo challenge model.…”

Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression

“…25), our findings add a cautionary note to adjuvanted HIV vaccines or other prevention approaches that induce ISGs at mucosal surfaces. Furthermore, while the rectum contains many resident target CD4 T cells 30 that antiviral mediators can protect, sites with few resident target cells, such as the female genital tract 16 , may depend on IFN-I signalling for CD4 T-cell recruitment and virus propagation. Thus, inflammation might attenuate transmission at the former site but exacerbate it at the latter 3 .…”

Mucosal Immunity and Vaccines Against Simian Immunodeficiency Virus and Human Immunodeficiency Virus

“…Target cell availability may play a key role in mucosal HIV transmission, and this has been shown to be a key factor in mother to infant transmission of SIV in sooty mangabeys and rhesus macaques (Chahroudi et al, 2014). We observed greater expression of CCR5 on macrophages in rectal rather than colon tissues in humans, and the availability of these HIV-1 target cells may contribute to greater risk of intrarectal transmission in men who have receptive anal sex with men (McElrath et al, 2013). The contribution of microbiome communities in the lower gastrointestinal and genitourinary tracts to local inflammation and immune responsiveness is under intensive investigation.…”