Abstract
Human immunodeficiency virus type 1 (HIV-1) infects and destroys cells of the immune system leading to an overt immune deficiency known as HIV acquired immunodeficiency syndrome (HIV/AIDS). The gut associated lymphoid tissue is one of the major lymphoid tissues targeted by HIV-1, and is considered a reservoir for HIV-1 replication and of major importance in CD4+ T-cell depletion. In addition to immunodeficiency, HIV-1 infection also directly causes gastrointestinal (GI) dysfunction, also known as HIV enteropathy. This enteropathy can manifest itself as many pathological changes in the GI tract. The objective of this study was to determine the association of gut HIV-1 infection markers with long-term survival in a cohort of men who have sex with men (MSM) enrolled pre-HAART (Highly Active Antiretroviral Therapy). We examined survival over 15-years in a cohort of 42 HIV-infected cases: In addition to CD4+ T cell counts and HIV-1 plasma viral load, multiple gut compartment (duodenum and colon) biopsies were taken by endoscopy every 6 months during the initial 3-year period. HIV-1 was cultured from tissues and phenotyped and viral loads in the gut tissues were determined. Moreover, the tissues were subjected to an extensive assessment of enteroendocrine cell distribution and pathology. The collected data was used for survival analyses, which showed that patients with higher gut tissue viral load levels had a significantly worse survival prognosis. Moreover, lower numbers of serotonin (duodenum) and somatostatin (duodenum and colon) immunoreactive cell counts in the gut tissues of patients was associated with significant lower survival prognosis. Our study, suggested that HIV-1 pathogenesis and survival prognosis is associated with altered enteroendocrine cell numbers, which could point to a potential role for enteroendocrine function in HIV infection and pathogenesis.
Highlights
Human immunodeficiency virus type 1 (HIV-1) infects and destroys cells of the immune system, which leads to CD4+ T-cell depletion and a profound immune deficiency known as Acquired Immunodeficiency Syndrome (HIV/AIDS)
As we found altered enteroendocrine cell numbers in the GI tract of HIV-1 infected individuals was closely linked to CD4+ T-cell counts, we examined if lower enteroendocrine cell numbers in the colon and duodenum, were in any way associated with altered survival probability
The GI tract is a major target and reservoir for HIV-1 replication, but many assumptions regarding HIV-1 infection of the gut have been based on the extrapolation of observations observed in the SIV model and acute HIV infection [2,3,4,5,6]
Summary
Human immunodeficiency virus type 1 (HIV-1) infects and destroys cells of the immune system, which leads to CD4+ T-cell depletion and a profound immune deficiency known as Acquired Immunodeficiency Syndrome (HIV/AIDS) (reviewed in [1]). HIV-related gut dysfunction and HIV associated mortality has been substantially reduced in the developed world since the introduction of highly active anti-retroviral therapy (HAART), many HIV-infected persons in resource-limited countries remain without treatment or receive suboptimal treatment Evidence from both the SIV macaque infection model and more limited studies in HIV-1 infected humans show that the pool of activated memory CD4+ CCR5+ CD4 cells in the GALT effectors site (i.e. lamina propria) are substantially depleted during primary SIV and HIV infection [3,20,21,22]. We used current and historic data from patients enrolled in a comprehensive prospective study of gut dysfunction in the pre-HAART era at the Southern Alberta HIV Clinic (SAC), Calgary, Alberta This cohort has been followed for more than 15 years, and we found that increased viral replication as well as altered enteroendocrine function was associated with reduced survival
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