Publications

The single greatest challenge to an HIV cure is the persistence of latently infected cells containing inducible, replication-competent proviral genomes, which constitute only a small fraction of total or infected cells in the body. Although resting CD4 T cells in the blood are a well-known source of viral rebound, more than 90% of the body's lymphocytes reside elsewhere. Many are in gut tissue, where HIV DNA levels per million CD4 T cells are considerably higher than in the blood. Despite the significant contribution of gut tissue to viral replication and persistence, little is known about the cell types that support persistence of HIV in the gut; importantly, T cells in the gut have phenotypic, functional, and survival properties that are distinct from T cells in other tissues. The mechanisms by which latency is established and maintained will likely depend on the location and cytokine milieu surrounding the latently infected cells in each compartment. Therefore, successful HIV cure strategies require identification and characterization of the exact cell types that support viral persistence, particularly in the gut. In this review, we describe the seeding of the latent HIV reservoir in the gut mucosa; highlight the evidence for compartmentalization and depletion of T cells; summarize the immunologic consequences of HIV infection within the gut milieu; propose how the damaged gut environment may promote the latent HIV reservoir; and explore several immune cell targets in the gut and their place on the path toward HIV cure.

The gastrointestinal (GI) tract harbors most of the body's immune cells and is also a major HIV reservoir in ART-treated patients. To achieve a cure, most HIV-infected cells must be identified and eliminated. While obtaining gut biopsies is a relatively noninvasive method of sampling relevant tissue for monitoring HIV activity, immune cell isolation from these limited tissue samples has proven to be challenging. Enzymatic tissue digestion is required for maximal immune cell isolation from gut biopsies. However, these enzymatic digestions can also be detrimental for preservation of cellular surface markers that are required for accurate identification of various subsets of leukocytes. In this study, we describe an optimized protocol for isolation of lymphocytes from human gut biopsies. We also discuss our validation results, which show that compared with several other collagenase preparations, the use of CSLPA maintains high lymphocyte recovery while preserving the integrity of most cellular surface antigens that we tested. Importantly, chemokine receptors that are used to characterize various subsets of T cells, which are notorious for being digested during a typical enzymatic tissue digestion, are highly preserved using this protocol.

Variants of the APOL1 gene, found primarily in individuals of African descent, are associated with various forms of kidney disease and kidney disease progression. Recent studies evaluating the association of APOL1 with cardiovascular disease have yielded conflicting results, and the potential role in cardiovascular disease remains unclear. In this review, we summarize the observational studies linking the APOL1 risk variants with chronic kidney and cardiovascular disease among persons of African descent.

BACKGROUND AND OBJECTIVES

The natural history of kidney disease among blacks who carry the high-risk variants varies, with only a subgroup progressing to ESRD. We aimed to determine whether the risk variants are associated with incident proteinuria in the context of hypertension-attributed CKD, and whether subsequent kidney function decline after the onset of proteinuria differs by risk status.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS

Using Cox models, we studied the association between risk status and incident proteinuria (defined as a doubling of urine protein-to-creatinine ratio to a level ≥0.22 g/g creatinine) among African-American Study of Kidney Disease and Hypertension (AASK) trial participants with genotyping and without proteinuria at baseline.

RESULTS

Of the 480 participants in our study, 82 (17%) had the high-risk genotypes (2 alleles), and 254 (53%) developed proteinuria over a median follow-up of 6.8 years. At baseline, mean eGFR was lower in the high-risk group compared with the low-risk group (0 or 1 allele; 49.6 versus 53.2 ml/min per 1.73 m, respectively; =0.02), but median proteinuria was similar (0.04 g/g creatinine for both groups; =0.43). Individuals with the high-risk genotypes were 1.72-fold more likely to develop incident proteinuria compared with those with the low-risk genotypes (95% confidence interval, 1.27 to 2.32), independent of age, sex, ancestry, baseline eGFR, baseline systolic BP, and randomized treatment groups. Although eGFR declined faster after the onset of proteinuria, this rate did not differ significantly by risk status.

CONCLUSIONS

Among blacks with established moderate CKD, the high-risk variants are associated with greater risk of incident proteinuria. After proteinuria onset, kidney function declines more rapidly but does not differ by risk status. This suggests that factors that lead to proteinuria, beyond , may additionally drive CKD progression.