APOL1 Variants Research Articles

Phenome-wide association analysis suggests the APOL1 linked disease spectrum primarily drives kidney-specific pathways

The relationship between commonly occurring genetic variants (G1 and G2) in the APOL1 gene in African Americans and different disease traits, such as kidney disease, cardiovascular disease, and pre-eclampsia, remains the subject of controversy. Here we took a genotype-first approach, a phenome-wide association study, to define the spectrum of phenotypes associated with APOL1 high-risk variants in 1,837 African American participants of Penn Medicine Biobank and 4,742 African American participants of Vanderbilt BioVU. In the Penn Medicine Biobank, outpatient creatinine measurement-based estimated glomerular filtration rate and multivariable regression models were used to evaluate the association between high-risk APOL1 status and renal outcomes. In meta-analysis of both cohorts, the strongest phenome-wide association study associations were for the high-risk APOL1 variants and diagnoses codes were highly significant for "kidney dialysis" (odds ratio 3.75) and "end stage kidney disease" (odds ratio 3.42). A number of phenotypes were associated with APOL1 high-risk genotypes in an analysis adjusted only for demographic variables. However, no associations were detected with non-renal phenotypes after controlling for chronic/end stage kidney disease status. Using calculated estimated glomerular filtration rate -based phenotype analysis in the Penn Medicine Biobank, APOL1 high-risk status was associated with prevalent chronic/end stage kidney disease /kidney transplant (odds ratio 2.27, 95% confidence interval 1.67-3.08). In high-risk participants, the estimated glomerular filtration rate was 15.4 mL/min/1.73m2; significantly lower than in low-risk participants. Thus, although APOL1 high-risk variants are associated with a range of phenotypes, the risks for other associated phenotypes appear much lower and in our dataset are driven by a primary effect on renal disease.

Abstract TP466: Apolipoprotein L1 Gene Risk Variants Are Not Associated With Increased Volume of Brain Lesions

Background: There are conflicting data regarding the association between apolipoprotein L1 gene (APOL1) risk variants and cardiovascular disease. Some data suggest a protective effect of APOL1 variants on subclinical atherosclerosis, despite an increase in the risk of kidney disease in African American patients. We sought to further explore this potentially paradoxical association. Methods: This is a secondary analysis of Systolic Blood Pressure Intervention Trial (SPRINT). We included African American patients who had APOL1 renal-risk variants genotyped. The primary outcome is volumetric measurements of lesions in four brain components: white matter (WM), gray matter (GM), basal ganglia (BG), and total brain (TB). The primary predictor is APOL1 risk genotype. We fit linear regression models to the primary outcomes and adjusted for age, sex, cigarette smoking, diabetes, hypertension, African ancestry admixture, and total brain volume. Results: We included 215 patients, with a mean (SD) age of 65.0 (7.8) years. The number of patients with 0, 1, and 2 APOL1 variants was 86, 105, and 24. The mean values for the volumetric measurements are seen in Table 1, which were not statistically different. The adjusted regression models did not show a significant relationship between APOL1 status and white matter lesions (β coef -0.36, 95% CI -1.20-0.48, p=0.398), gray matter lesions (β coef -0.002, 95% CI -0.07-0.07, p=0.945), basal ganglia lesions (β coef -0.01, 95% CI -0.03-0.02, p=0.542), or total brain lesions (β coef -0.36, 95% CI -1.21-0.49, p=0.403). Conclusion: There is no association between APOL1 risk variants and brain lesions in African American patients. These data support prior studies that found no relationship between APOL1 and chronic microvascular disease or brain volume. Despite these findings, further research would be needed to fully disprove an association, given conflicting reports in the literature and the smaller sample size of this study.

Collapsing Focal Segmental Glomerulosclerosis and Acute Oxalate Nephropathy in a Patient With COVID-19: A Double Whammy

As COVID-19 (coronavirus disease 2019) spreads across the world multiple therapeutic interventions have been tried to reduce morbidity and mortality. We describe a case of collapsing focal sclerosing glomerulosclerosis (FSGS) and acute oxalate nephropathy in a patient treated with high-dose intravenous vitamin C for severe COVID-19 infection. Collapsing FSGS has been described in patients with COVID-19 infection associated with APOL-1; however, this case had collapsing FSGS developing in low-risk heterozygous APOL-1 variant, and we postulate that the intensity of the COVID-19 cytokine storm overwhelmed the protective state of APOL-1 heterozygosity. This case illustrates the importance of assessing the risk and benefit of planned therapeutic interventions on a case-by-case basis especially when there are still so many unknowns in the management of COVID-19 infection. Strong consideration should be given for performing a renal biopsy in patients who develop multifactorial acute kidney injury.

Prevalence of APOL1 Risk Variants in Afro-Descendant Patients with Chronic Kidney Disease in a Latin American Country.

Introduction In Colombia, the genetic background of the populations was shaped by different levels of admixture between Natives, European, and Africans. Approximately 35.363 patients have diagnosed chronic kidney disease and according to population studies, 10.4% of these patients are Afro-descendant. We aim to assess the frequency of APOL1 variants G1 and G2 in Afro-descendant patients with ESRD treated at la Fundacion Valle del Lili University Hospital in Cali, Colombia. Methods This is an observational cross-sectional study. Afro-descendant patients with ESRD in waitlist or recipients of kidney transplant were evaluated. Clinical data were collected from the electronic medical records. Genotyping was carried out by amplification of the exon 7 of the APOL1 gene. For the identification of risk genotypes, the bioinformatics tool BLAST was used. Results We enrolled 102 participants. The frequency of APOL1 risk variants was 67.2%, in which 24.5% (n = 25) were G1 heterozygous and 5.8% (n = 6) were G2 heterozygous and 37% of the patients had high-risk status with two alleles in homozygous (G1/G1 = 21 and G2/G2 = 3) or compound heterozygote (G1/G2 = 14) form.

Genetic Testing for APOL1 Genetic Variants in Clinical Practice: Finally Starting to Arrive.

The identification of genetic variants in APOL1 as a major driver of kidney disease in blacks has ushered in an exciting new era in glomerular disease, offering the potential for precision medicine in a range of kidney diseases in individuals with sub-Saharan African ancestry ([1][1]). The presence

The podocin V260E mutation predicts steroid resistant nephrotic syndrome in black South African children with focal segmental glomerulosclerosis

In black African children with focal segmental glomerulosclerosis (FSGS) there are high rates of steroid resistance. The aim was to determine genetic associations with apolipoprotein L1 (APOL1) renal risk variants and podocin (NPHS2) variants in 30 unrelated black South African children with FSGS. Three APOL1 variants were genotyped and the exons of the NPHS2 gene sequenced in the cases and controls. APOL1 risk alleles show a modest association with steroid sensitive nephrotic syndrome (SSNS) and steroid resistant nephrotic syndrome (SRNS). The NPHS2 V260E variant was present in SRNS cases (V/V = 5; V/E = 4; E/E = 11), and was absent in SSNS cases. Haplotype analysis suggests a single mutation origin for V260E and it was associated with a decline in kidney function over a 60-month period (p = 0.026). The V260E variant is a good predictor of autosomal recessive SRNS in black South African children and could provide useful information in a clinical setting.

Apolipoprotein L1 associated nephropathy; an overview

Genetic variants of apolipoprotein L1 (APOL1) have been recognized as a risk factor for kidney disease in people of African ancestry. APOL1 mediate renal damage in podocytes through necrosis, apoptosis and pyroptosis processes. APOL1 gene contains G1 and G2 alleles that mediate in increasing risk of renal disorders in African Americans. People who carry APOL1 risk alleles have a three to four-fold increase risk for non-diabetic renal disease (NDRD), Idiopathic focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy (HIVAN). Therefore, identifying genetic factors involved in the pathogenesis of renal disorders, including APOL1 risk variants, may help to improve our understanding of kidney problems.

APOL1 Kidney Risk Variants Induce Cell Death via Mitochondrial Translocation and Opening of the Mitochondrial Permeability Transition Pore

Genetic Variants in Apolipoprotein L1 (APOL1) are associated with large increases in CKD rates among African Americans. Experiments in cell and mouse models suggest that these risk-related polymorphisms are toxic gain-of-function variants that cause kidney dysfunction, following a recessive mode of inheritance. Recent data in trypanosomes and in human cells indicate that such variants may cause toxicity through their effects on mitochondria. To examine the molecular mechanisms underlying APOL1 risk variant-induced mitochondrial dysfunction, we generated tetracycline-inducible HEK293 T-REx cells stably expressing the APOL1 nonrisk G0 variant or APOL1 risk variants. Using these cells, we mapped the molecular pathway from mitochondrial import of APOL1 protein to APOL1-induced cell death with small interfering RNA knockdowns, pharmacologic inhibitors, blue native PAGE, mass spectrometry, and assessment of mitochondrial permeability transition pore function. We found that the APOL1 G0 and risk variant proteins shared the same import pathway into the mitochondrial matrix. Once inside, G0 remained monomeric, whereas risk variant proteins were prone to forming higher-order oligomers. Both nonrisk G0 and risk variant proteins bound components of the mitochondrial permeability transition pore, but only risk variant proteins activated pore opening. Blocking mitochondrial import of APOL1 risk variants largely eliminated oligomer formation and also rescued toxicity. Our study illuminates important differences in the molecular behavior of APOL1 nonrisk and risk variants, and our observations suggest a mechanism that may explain the very different functional effects of these variants, despite the lack of consistently observed differences in trafficking patterns, intracellular localization, or binding partners. Variant-dependent differences in oligomerization pattern may underlie APOL1's recessive, gain-of-function biology.

Promises and pitfalls of whole-exome sequencing exemplified by a nephrotic syndrome family

High-throughput techniques such as whole-exome sequencing (WES) show promise for the identification of candidate genes that underlie Mendelian diseases such as nephrotic syndrome (NS). These techniques have enabled the identification of a proportion of the approximately 54 genes associated with NS. However, the main pitfall of using WES in clinical and research practice is the identification of multiple variants, which hampers interpretation during downstream analysis. One useful strategy is to evaluate the co-inheritance of rare variants in affected family members. Here, we performed WES of a patient with steroid-resistant NS (SRNS) and intermittent microhematuria. Currently, 15years after kidney transplantation, this patient presents normal kidney function. The patient was found to be homozygous for a rare MYO1E stop-gain variant, and was heterozygous for rare variants in NS-associated genes, COL4A4, KANK1, LAMB2, ANLN, E2F3, and APOL1. We evaluated the presence or absence of these variants in both parents and 11 siblings, three of whom exhibited a milder phenotype of the kidney disease. Analysis of variant segregation in the family, indicated the MYO1E stop-gain variant as the putative causal variant underlying the kidney disease in the patient and two of her affected sisters. Two secondary variants in COL4A4-identified in some other affected family members-require further functional studies to determine whether they play a role in the development of microhematuria in affected family members. Our data illustrate the difficulties in distinguishing the causal pathogenic variants from incidental findings after WES-based variant analysis, especially in heterogenous genetic conditions, such as NS.

APOL1 high-risk genotypes and renal transplantation.

The discovery of apolipoprotein L1 (APOL1) gene variants and its association with kidney disease in African-Americans represent a significant breakthrough in understanding the genetic basis of ancestry-based differences in a public health problem. The role these variants play in renal transplantation is still incompletely understood. This article reviews the epidemiologic data and current reports of APOL1 variant pathogenesis in transplantation. We examine existing data on outcomes in APOL1 high-risk kidneys, high-risk APOL1 recipients, live donors with high-risk mutations and non-renal transplantation of high-risk APOL1 organs. We discuss the rapidly evolving role and potential pros and cons of APOL1 genotyping of donors and recipients in transplantation. Finally, we highlight the ongoing nationwide National Institutes of Health-sponsored "APOL1 Long-term Kidney Transplantation Outcomes (APOLLO)" study, which will quantify outcomes and "second hits" in pertinent to APOL1 high-risk variants in renal transplantation.

Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study

BackgroundChronic kidney disease (CKD) is common and disproportionally burdens United States ethnic minorities. Its genetic determinants may differ by disease severity and clinical stages. To uncover genetic factors associated CKD severity among high-risk ethnic groups, we performed genome-wide association studies (GWAS) in diverse populations within the Population Architecture using Genomics and Epidemiology (PAGE) study.MethodsWe assembled multi-ethnic genome-wide imputed data on CKD non-overlapping cases [4,150 mild to moderate CKD, 1,105 end-stage kidney disease (ESKD)] and non-CKD controls for up to 41,041 PAGE participants (African Americans, Hispanics/Latinos, East Asian, Native Hawaiian, and American Indians). We implemented a generalized estimating equation approach for GWAS using ancestry combined data while adjusting for age, sex, principal components, study, and ethnicity.ResultsThe GWAS identified a novel genome-wide associated locus for mild to moderate CKD nearby NMT2 (rs10906850, p = 3.7 × 10-8) that replicated in the United Kingdom Biobank white British (p = 0.008). Several variants at the APOL1 locus were associated with ESKD including the APOL1 G1 rs73885319 (p = 1.2 × 10-9). There was no overlap among associated loci for CKD and ESKD traits, even at the previously reported APOL1 locus (p = 0.76 for CKD). Several additional loci were associated with CKD or ESKD at p-values below the genome-wide threshold. These loci were often driven by variants more common in non-European ancestry.ConclusionOur genetic study identified a novel association at NMT2 for CKD and showed for the first time strong associations of the APOL1 variants with ESKD across multi-ethnic populations. Our findings suggest differences in genetic effects across CKD severity and provide information for study design of genetic studies of CKD in diverse populations.

One Actor, Many Roles: Histopathologies Associated With APOL1 Genetic Variants.

Genetic variants in APOL1, encoding apolipoprotein L1, are major drivers of glomerular disease in peoples of sub-Saharan African descent. APOL1-associated primary glomerular diseases include focal segmental glomerulosclerosis, human immunodeficiency virus-associated nephropathies, and arterionephrosclerosis. Other conditions where APOL1 variants affect outcomes include membranous nephropathy, lupus nephritis, diabetic nephropathy, preeclampsia, and kidney transplant. In focal segmental glomerulosclerosis, APOL1 variants are associated with upregulation of RNA encoding chemokine C-X-C motif receptor 3 ligands and ubiquitin D; the significance of these findings remains unclear but may provide valuable insight into disease mechanisms.

Nucleosomal double-stranded DNA triggers APOL1 expression through the STINGTBK1-IRF3 pathway

Abstract African Americans are four times more likely to develop kidney disease. Racial disparities in the frequency of nondiabetic kidney disease has led to the discovery of the apolipoprotein L1 (APOL1) gene variants, G1 and G2, which exist exclusively in individuals of recent African ancestry. The presence of these kidney risk alleles strongly correlates with several forms of nondiabetic kidney disease including lupus nephritis (LN). However, the mechanism by which APOL1 variants lead to a faster progression to LN in systemic lupus erythematosus (SLE) patients carrying APOL1 risk alleles is unclear. Increased levels of type I interferons (IFNs) and nucleosomal dsDNA fragments (nsDNA) in the blood is the hallmark of lupus erythematosus. We hypothesize that accumulation of dsDNA in the cytosol of podocytes that play a key role in maintenance of the filtration barrier in the kidney activates the DNA sensing pathways leading to expression of type I IFNs and proinflammatory cytokines damaging podocytes. Although type I IFNs stimulate APOL1 expression, it is unknown whether dsDNA induces APOL1 accumulation independently of IFN. Here we show that nsDNA triggers the expression of APOL1 through the activation of the cGAS/IFI16-STING-TBK1-IRF3 pathway. We have also shown that inhibition of type I IFN only partly inhibited APOL1 accumulation in podocytes, demonstrating that nsDNA directly activates expression of the APOL1 gene. We conclude that blocking type I IFN signaling and targeting elements of the nsDNA-induced pathway may represent a novel therapeutic approach to inhibit LN progression in African Americans SLE patients carrying APOL1 kidney risk alleles.

APOL1, Acid Load, and CKD Progression

IntroductionHigh dietary acid load and metabolic acidosis are associated with an accelerated decline in kidney function and may contribute to the observed heterogeneity in end-stage renal disease (ESRD) risk according to APOL1 genotype. Our objective was to examine the associations of metabolic acidosis and dietary acid load with kidney disease progression, according to APOL1 genotype, among individuals with chronic kidney disease (CKD).MethodsWe studied 1048 African American participants in the Chronic Renal Insufficiency Cohort. Metabolic acidosis was defined as blood levels of serum bicarbonate less than 22 mEq/L, and dietary acid load was quantified by potential renal acid load (PRAL) using data from the Diet Health Questionnaire. APOL1 status was defined as having 2 risk variants, consisting of either possible combination of the G1 and G2 risk alleles. We tested associations of APOL1 and dietary and metabolic acidosis with CKD progression, defined as time to ESRD or 50% decline in eGFR.ResultsDuring a median follow-up period of 7 years, 379 participants had an incident CKD progression event (6.4 events per 100 person-years). After full adjustment, among participants with 2 APOL1 variants, the analysis failed to detect an association between metabolic acidosis or dietary acid load and CKD progression (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.96–1.11 per 1 mEq/L higher serum bicarbonate and an HR, 1.03; 95% CI, 0.92–1.15 per 10 mEq/L higher PRAL). Similar associations were noted among participants without the APOL1 high-risk genotype.ConclusionIn a population at high risk of developing ESRD, metabolic acidosis and dietary acid load were not associated with CKD progression.

Burden, access and disparities in kidney disease: chronic kidney disease hotspots and progress one step at a time.

The 2019 International Society of Nephrology World Kidney Day theme is Kidney Health for Everyone Everywhere. It focuses on the uneven burden of acute kidney injury and chronic kidney disease (CKD) in different communities, identifies disparities and challenges in access to care and calls for universal health coverage for prevention and early treatment of kidney disease. This topic is fully in line with the Clinical Kidney Journal (ckj) editorial strategy for improving worldwide kidney care without leaving any community behind. Indeed, the first PubMed-recorded use of the term CKD hotspot was in ckj, where it was defined as ‘countries, region[s], communities or ethnicities with higher than average incidence of CKD’. This issue of ckj contains the World Kidney Day editorial as well as contributions that illustrate two concepts: the need to validate biochemical thresholds generated in developed countries in other populations, as exemplified by Kidney Disease: Improving Global Outcomes CKD–mineral and bone disorder parameters in an African population, and the fact that some disease associations characteristic of developing countries may be described initially in developed countries, as exemplified by the association of APOL1 variants with CKD or by minimal change disease secondary to malaria, but have to be validated locally.

Reassessing the risk of kidney organ donation: Researchers are taking a closer look at the long-term health risks that living kidney donors may face to refine the informed consent process and improve follow-up care.

Reassessing the risk of kidney organ donation: Researchers are taking a closer look at the long-term health risks that living kidney donors may face to refine the informed consent process and improve follow-up care.

The Impact of APOL1 on Chronic Kidney Disease and Hypertension.

Essential hypertension is a clinical diagnosis based on the presence of an elevated systemic blood pressure on physical examination without a clear inciting cause. It has multiple etiologies and is not a homogeneous disorder. Hypertension contributes to the development and progression of atherosclerotic cardiovascular diseases, and antihypertensive treatment reduces the risk of fatal and nonfatal myocardial infarction, stroke, and congestive heart failure. Although hypertension is frequently present in nondiabetic individuals with low levels of proteinuria and chronic kidney disease, reducing blood pressures in this population does not reliably slow nephropathy progression. Many of these patients with recent African ancestry have the primary kidney disease "solidified glomerulosclerosis" that is strongly associated with renal-risk variants in the apolipoprotein L1 gene (APOL1). This kidney disease contributes to secondarily elevated blood pressures. The APOL1-associated spectrum of nondiabetic nephropathy also includes proteinuric kidney diseases, idiopathic focal segmental glomerulosclerosis, collapsing glomerulopathy, severe lupus nephritis, and sickle cell nephropathy. This article reviews relationships between mild to moderate essential hypertension and chronic kidney disease with a focus on the role of APOL1 in development of hypertension. Available evidence strongly supports that APOL1 renal-risk variants associate with glomerulosclerosis in African Americans, which then causes secondary hypertension, not with essential hypertension per se.

3448 Macrophages, APOL1 Genotype, & Immunometabolism in CVD (MAGIC

OBJECTIVES/SPECIFIC AIMS: This study aims to understand the potential immunomudualtory effect of APOL1 variants in auto-antigen activated myeloid cells by assessing lysosomal integrity in activated cells expressing APOL1. The primary stimuli were: 1. ssRNA hY3 as a proxy for the Ro immune complex; 2. in an bulk RNA seq model, interferon-response gene, Siglec 1, as a read out of interferon activity. The primary outcomes were: 1. Myeloid cell APOL1 expression both in primary macrophage cultures and ex-vivo patient derived macrophages; 2. Lysosome integrity as measured by fluorescence intensity of lysotracker dye on light microscopy. METHODS/STUDY POPULATION: All recruited subjects provided written informed consent as per the NEW YORK UNIVERSITY Division of Rheumatology-wide Specimen and Matched Phenotype Linked Examination (SAMPLE) protocol. Subjects were African American; SLE subjects met 4 American College of Rheumatology criteria for SLE. Healthy donor monocytes representing each genotype in duplicate (reference allele: G0/G0; heterozygote variant: RV/G0; and homozygote variant RV/RV) were cultured with GM-CSF to yield macrophages which were incubated in serum free media or with hY3 ssRNA (TLR 7/8 agonist) to yield inflammatory M1 macrophages. Fold increase of APOL1 in untreated vs hY3 treated macrophages was measured using qPCR. Live cells were then cultured on glass chamber slides with DNA dye, DAPI, and Lysotracker red, a fluorescent dye that stains acidic lysosomes. As a proof of concept, interferon response gene, Signlec1, and APOL1 transcriptional activity in peripheral blood monocytes (PBMCs) were measured and correlated in 17 SLE patients by RNA seq. RESULTS/ANTICIPATED RESULTS: Regardless of genotype, hY3 increased APOL1 expression by 29 (+/−18.4) fold (P = 0.007 vs no treatment). Genotyping of the qPCR product showed concordance with the chromosomal DNA with the RV heterozygotes expressing both alleles. To examine lysosomal membrane integrity, live hY3-treated macrophages were stained with lysosotracker dye and fluorescence intensity was measured. Compared to reference allele carrying macrophages, each additional variant allele corresponded with a lesser degree of lysosome compartment staining. In SLE PBMCs, we found that APOL1 was highly expressed, and significantly correlated with Siglec1 (F=10.5; P = 0.005) supporting an association between circulating interferons and APOL1 accumulation in monocytes. DISCUSSION/SIGNIFICANCE OF IMPACT: Given that the “cytokine milieu” in SLE elicits APOL1 expression, induces inflammatory cell metabolic rewiring, and stimulates autophagy thereby exposing defects in autophagic flux, this gene-environment interaction may underpin the relationship between chronic inflammation and heightened APOL1 polymorphism-attributed cardiovascular risk. These data support further inquiry into the intersection between chronic autoimmunity and APOL1’s functional role in the vascular microenvironment. The in vitro studies herein extend our prior work by demonstrating a mechanistic link between SLE-associated inflammation, APOL1 risk variant status and CVD via a lysosomal defect which converges on common autophagic and metabolic pathways in mononuclear cells.

Apolipoprotein L1 and kidney transplantation.

Consistent associations between variants of the apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy have been reported in individuals of African descent. Donor APOL1 genotype has also been linked to shorter renal allograft survival. This review summarizes recent advances in understanding the biology of APOL1 and their implications to kidney donors and recipients. Approximately 12-13% of African Americans have two renal risk APOL1 variants but most do not develop kidney disease. Although the exact mechanisms linking APOL1 genotype to renal injury are not known, evidence from new experimental models suggests APOL1 mutations may accelerate age-related podocyte loss. Recent epidemiological studies indicate potential kidney donors with high-risk APOL1 variants have increased risk of chronic kidney disease (CKD) and donors with high-risk APOL1 variants have lower estimated glomerular filtration rate (eGFR) than those with low-risk variants. The absolute risk of CKD in otherwise healthy individuals carrying high-risk APOL1 mutations is likely low. Recent studies suggest high-risk APOL1 mutations in kidney donors are linked to shorter graft survival and lower postdonation eGFR. APOL1 genotyping may be used as one of many factors that contribute to assessment of the risk of postdonation CKD and informed decision making.

Impact of APOL1 Genetic Variants on HIV-1 Infection and Disease Progression.

Apolipoprotein L1 (APOL1) has broad innate immune functions and has been shown to restrict HIV replication in vitro by multiple mechanisms. Coding variants in APOL1 are strongly associated with HIV-associated nephropathy (HIVAN) in persons with untreated HIV infection; however, the mechanism by which APOL1 variant protein potentiates renal injury in the presence of high viral load is not resolved. Little is known about the association of APOL1 genotypes with HIV viral load, HIV acquisition, or progression to AIDS. We assessed the role of APOL1 coding variants on HIV-1 acquisition using the conditional logistic regression test, on viral load using the t-test or ANOVA, and on progression to AIDS using Cox proportional hazards models among African Americans enrolled in the ALIVE HIV natural history cohort (n = 775). APOL1 variants were not associated with susceptibility to HIV-1 acquisition by comparing genotype frequencies between HIV-1 positive and exposed or at-risk HIV-1 uninfected groups (recessive model, 12.8 vs. 12.5%, respectively; OR 1.02, 95% CI 0.62–1.70). Similar null results were observed for dominant and additive models. APOL1 variants were not associated with HIV-1 viral load or with risk of progression to AIDS [Relative hazards (RH) 1.33, 95% CI 0.30–5.89 and 0.96, 95% CI 0.49–1.88, for recessive and additive models, respectively]. In summary, we found no evidence that APOL1 variants are associated with host susceptibility to HIV-1 acquisition, set-point HIV-1 viral load or time to incident AIDS. These results suggest that APOL1 variants are unlikely to influence HIV infection or progression among individuals of African ancestry.