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. Author manuscript; available in PMC: 2022 Mar 1.
Published in final edited form as: AIDS. 2021 Mar 1;35(3):359–367. doi: 10.1097/QAD.0000000000002753

HIV-1 infection of the kidney: mechanisms and implications

Kelly Hughes 1,2, Jerry Chang 1,2, Hannah Stadtler 1,2, Christina Wyatt 3, Mary Klotman 1,2,*, Maria Blasi 2,3,*
PMCID: PMC7855797  NIHMSID: NIHMS1656540  PMID: 33229896

Abstract

People living with HIV are at higher risk for acute and chronic kidney disease compared to uninfected individuals. Kidney disease in this population is multifactorial, with several contributors including HIV infection of kidney cells, chronic inflammation, genetic predisposition, aging, comorbidities, and coinfections. In this review, we provide a summary of recent advancements in the understanding of the mechanisms and implications of HIV infection and kidney disease, with particular focus on the role of direct HIV infection of renal cells.

Introduction

Kidney injury is an important complication of HIV infection. Several mechanisms may contribute to kidney disease in people living with HIV (PLWH), including direct injury related to intrarenal HIV infection and gene expression, immune dysregulation, treatment toxicity, co-morbidities, and co-infections [1]. HIV-associated nephropathy (HIVAN) was the most common kidney disease in PLWH before anti-retroviral therapy (ART) was available [2]. Animal models and human biopsy studies have established the causal relationship between HIVAN and direct HIV infection of renal epithelial cells (Figure 1), expression of viral genes in the kidney, and dysregulation of host genes involved in cell differentiation and cell cycle [3–8]. Without ART HIVAN quickly progresses to end-stage renal disease [9]; however, ART administration early in the course of HIVAN stabilizes renal function and improves prognosis, consistent with a direct role for renal HIV infection in renal pathology. Although HIVAN is less common with the widespread use of ART, it nonetheless remains an important cause of kidney disease in the setting of delayed HIV diagnosis or non-adherence to ART [10].

Figure 1. HIV-1 infection of the renal epithelium.

Figure 1.

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Adapted from Ross et al. [8] with permission. HIV-1 nucleic acids (indicated by the black arrows) are demonstrated by RNA in situ hybridization (a) and DNA in situ PCR (b) in a kidney biopsy from a patient with HIVAN. Magnification, × 60

Other kidney diseases, including immune complex kidney diseases, antiretroviral nephrotoxicity, and comorbid kidney disease due to diabetes and hypertension have become increasingly common with aging of the HIV population. [8] End-stage renal disease (ESRD) has been shown to occur at a younger age in PLWH than in HIV-negative individuals [11], and PLWH may also have worse outcomes on dialysis [12, 13]. Early in the epidemic, kidney transplantation was not an option for PLWH because of concerns about the risk of opportunistic infections and uncertainty about allocating a scarce resource to a group in which outcomes and survival benefit were unknown [14]. Observational studies have demonstrated that PLWH can be safely transplanted with good outcomes [15–17], although acute allograft rejection is more common and may impact long-term allograft survival rates [15]. More recently, data from South Africa support the use of HIV+ donor organs[16], although additional research is needed to evaluate the safety of this approach in populations with higher rates of ART resistance. Recent studies in HIV+ kidney transplant recipients have also highlighted the possibility that the kidney serves as a reservoir for the virus [5, 18], although the potential impact on long-term allograft survival and implications for the design of HIV cure strategies remain unknown.

In this review we provide an overview of recent developments in our understanding of genetic susceptibility to kidney disease in PLWH, the in vivo evidence supporting the kidney as a potential viral reservoir, and the in vitro studies elucidating the mechanisms of viral infection of renal epithelial cells.

Incidence and clinical presentation of kidney disease in PLWH

Acute Kidney Injury (AKI), defined by a rapid decline in kidney function as indicated by an increased serum creatinine level, is more common among HIV+ individuals than it is in the general population, and is associated with an increased risk for other complications including heart failure, cardiovascular disease, ESRD, and death [19]. Among hospitalized PLWH, incidence of AKI is associated with increased mortality [19, 20].

HIVAN is the classic kidney disease associated with HIV infection and is clinically characterized by rapidly progressive kidney failure, often accompanied by significant proteinuria in patients with advanced HIV disease [21] (Table 1). Histologically, it is distinguished by collapsing focal segmental glomerulosclerosis (FSGS), microcystic tubular dilation, and interstitial infiltration; it is also distinguished by cellular abnormalities, including hypertrophy, polyploidy, and apoptosis [21, 22]. Sequential biopsies taken during acute HIVAN and recovery following ART initiation demonstrate significant improvement in pathology, including reduction of inflammatory infiltrate, reduction in the severity of tubulointerstitial disease, disappearance of microcysts, and reduction of cellular abnormalities [9]. Despite these improvements, FSGS may persist. While the incidence of HIVAN has decreased as a result of successful ART, chronic kidney disease (CKD) remains an important co-morbidity for many PLWH. HIV infection is recognized as an independent risk factor for developing CKD, and, in addition to the traditional risk factors such as genetic predisposition, diabetes, hypertension and environmental factors, PLWH are also at increased risk for kidney disease due to ART nephrotoxicity [23–25]. The incidence of CKD among PLWH is also increasing due to the advancing age of this population, whose life expectancies now approximate those of the general population thanks to widespread use of ART [24, 26].

Table 1.

Clinical and pathologic characteristics of HIVAN.

Typical clinical presentation CD4+ cell counts < 200 cells/mm3
Detectable HIV-RNA
Proteinuria without active urine sediment
Rapid decline in glomerular filtration rate
Enlarged and echogenic kidneys at ultrasound
Pathologic presentation Collapsing glomerulopathy
 Hypertrophy and hyperplasia of podocytes
 Podocyte cell cycle dysregulation
Tubular microcysts
 Tubular atrophy
 Hypertrophy and polyploidy of tubular epithelial cells
 Proteinaceous casts
Interstitial fibrosis and inflammation
 Interstitial leukocytes
  (CD4, CD8, monocytes/macrophages)
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Genetic predisposition in HIV-related kidney disease

The risk of developing kidney disease is substantially higher in persons of African descent compared to other ethnic groups [27], and this risk is magnified in PLWH. This racial difference has been linked to variants in the apolipoprotein L1 (APOL1) gene (Table 2), a member of the APOL gene family presumed to play a role in innate immunity [28]. Compared to wild type (G0), the two variants (G1 and G2) are associated with an increased risk of kidney disease [29, 30]. These variants are unique to individuals of African descent, and may have been recently selected in Africa as a defense mechanism against trypanosome infection [28]. Both variants confer an immunological advantage against trypanosomiasis [31], but increase the risk for HIV-associated kidney disease [32]. These variants are inherited in a recessive manner, and in a heterozygous state, protect against trypanosomes but in a homozygous (G1,G1 or G2,G2), or compound heterozygous state (G1,G2) confer an increased risk for kidney disease [30, 33]. Notably, these APOL1 variants are largely absent in Ethiopia and East Africa, and HIVAN is not seen in these populations [34, 35].

Table 2.

Evidence supporting APOL1 genotype and risk of kidney disease.

Findings References
Discovery of genetic variants in the APOL1 gene that explained the higher rate of kidney failure in African Americans compared to Americans of European descent [30, 31, 77]
APOL1 risk variants strongly associated with HIV-associated nephropathy in Black South Africans [36, 37]
APOL1 risk variants associated with end-stage renal disease in African Americans with lupus nephritis. [78]
Two APOL1 risk alleles confer strong risk for the development of collapsing glomerulopathy in African Americans [79]
APOL1 mutations associated with a distinct category of kidney disease that manifests at younger ages in African ancestry populations. [80]
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Individuals with a high risk APOL1 genotype have a 7 to 10-fold increased risk for developing non-HIV associated FSGS and hypertension-attributed ESRD [29, 30]. In the setting of HIV infection, these genetic variants dramatically increase the risk of developing HIVAN by 29-fold in African Americans and as much as 89-fold in South Africans [36, 37].

The mechanisms of APOL1-mediated kidney injury are not yet fully understood. APOL1 is expressed in numerous tissues and can be found circulating in plasma, due primarily to secretion by the liver [38]. However, plasma APOL1 levels do not correlate with kidney disease [39, 40]. Data from transplant studies suggest that the presence of APOL1 high-risk variants in the organ donor, rather than in the transplant recipient, determines the risk of subsequent disease [41, 42]. Together, these reports strongly suggest that, in those with high-risk APOL1 variants, kidney injury effects are likely mediated locally, within the kidney.

In vivo evidence to support the kidney as a site of HIV replication and persistence

HIV-1 infection and persistence in different organs and tissues can result in the generation of distinct viral populations, viral compartments, and reservoirs. Viral compartments restrict HIV-1 trafficking and gene flow, and facilitate separate viral evolution diverging from viral lineages in the peripheral blood or other anatomical sites [43–45]. Increasing evidence supports the kidney as a separate viral compartment, as suggested by the comparison of viral sequences amplified from blood to those derived from kidney tissue [4, 18] and urine [18, 46]. In addition to demonstrating the presence of genetically distinct viruses in urine, those studies also demonstrated the presence of several identical sequences, suggesting that the source of those urine-derived viruses may be a population of clonally expanded cells in the genitourinary tract, similarly to what has been described for infected T cells in the bloodstream [47, 48].

Additional evidence on the potential role of the kidney as a site of HIV replication and persistence (Table 3) comes from studies in HIV+ kidney transplant recipients.

Table 3.

Evidence supporting the kidney as a reservoir for HIV-1.

Findings References
Detection of HIV-1 nucleic acids in renal biopsies of patients with HIVAN [3, 4, 9, 81–83]
Phylogenetic analysis of HIV-1 sequences in kidney biopsies of patients with HIVAN [4]
HIV-1 shedding and sequence compartmentalization in urine of PLWH [46, 84]
Infection of HIV-1 negative allograft kidneys in PLWH undergoing kidney transplantation [5]
Detection of donor and recipient HIV-1 strains in urine, renal epithelial cells and allograft kidney biopsy following HIV+ to HIV+ kidney transplantation [18]
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A 2014 study conducted on HIV positive individuals that received a kidney transplant from HIV negative donors, demonstrated that 68% of the previously uninfected allografts became infected with HIV, even though all the recipients had very well controlled viral loads on ART [5]. Biopsies taken at 3 and 12 months post-transplant demonstrated the presence of HIV-RNA in both podocytes and renal tubule epithelial (RTE) cells[5]. Podocyte infection was associated with podocyte apoptosis and more rapid decline in kidney function, while infection of renal tubule epithelial cells was more frequently associated with tubulointerstitial inflammation [5]. These findings could explain the reduced long-term allograft survival rates among HIV+ transplant recipients [15].

More recently, due to the approval of the HIV Organ Policy Equity (HOPE) Act [49], HIV+ individuals in the United States can opt to receive a kidney from other individuals with HIV, which increases the pool of organs available for transplant, and thus provides an important alternative to dialysis for those relegated to long transplant waitlists [50]. The implementation of HIV+ to HIV+ kidney transplantations, which was pioneered in South Africa in 2008 [51], has also provided an opportunity to further address the potential for the kidney to serve as a viral reservoir and to study the viral dynamics post-transplantation.

Three of the 27 subjects enrolled in the South Africa study developed recurrent HIV-associated nephropathy [16], consistent with HIV-1 infection of the kidney.

In a recent study from our group, we reported the detection of donor virus in urine and urine-derived RTE cells of the kidney transplant recipient up to 2 weeks post-transplantation despite ART [18] in the recipient. A few viral sequences (n=2) corresponding to the donor HIV strain were also detected in the recipient blood only at day 3 post-transplantation. In addition, several HIV sequences were also amplified from the donor’s pre-implantation kidney-biopsy sample, which further indicated the presence of infection in the allograft, although it does not indicate the intrarenal cell source. These findings demonstrate that the donor HIV strain, harbored in the donor kidney, can be transferred and be detected in the recipient. Longitudinal follow-up studies of these transplant recipients are needed to understand the longer term viral dynamics in patients potentially harboring two separate strains of HIV-1 and the impact of renal HIV infection on the long-term survival of the allograft.

Use of in vitro models to study renal HIV infection

Although it is established that renal cells (both podocytes and RTE cells) become infected with HIV in vivo, the precise mechanisms by which this happens remain elusive. A number of in vitro studies by our group and others have shed light on potential pathways.

HIV entry into renal cells occurs in a CD4-independent manner, as neither podocytes nor RTE cells express CD4 nor the CCR5 and CXCR4 co-receptors [52, 53] used by HIV to infect immune cells including CD4+ T cells and macrophages. Lipid rafts have been implicated in CD4-independent entry of HIV into podocytes [54], as has DC-SIGN, however these entry pathways did not result in productive infection of podocytes [55]. Similarly, the DEC-205 receptor has been reported to mediate internalization of HIV into RTE cells without establishing productive infection [53].

Conversely, productive infection of renal cells has been demonstrated in the setting of direct cell-cell interaction with both infected CD4+ T cells and macrophages [56, 57]. Examination of the interaction between HIV-infected CD4+ T cells and RTE cells revealed the formation of virological synapses, which could allow the transfer of virus from CD4+ T cells to RTE cells (Figure 2 A) [58]. In the same studies it was shown that heparan sulfate proteoglycans (HSP) might be involved in this transfer, as the use of HSP inhibitors significantly reduced infection of RTE cells [58]. Interestingly, these studies also showed that the HIV envelope glycoprotein is not involved in virus transfer from one cell type to the other [56, 58, 59]. Importantly, infected RTE cells were in turn capable of mediating infection of CD4+ T cells and monocytes, suggesting a bi-directional infection model between immune cells and RTE cells that can establish and propagate HIV infection in renal tissue (Figure 2 A)[56, 57].

Figure 2. Cellular connections allowing cell-to-cell spread of HIV-1 within the kidney.

Figure 2.

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(A) In vitro studies have demonstrated that the formation of virological synapses and tunneling nanotubes between CD4+ T cells, macrophages and renal cells allow HIV-1 spread among these different cell types. (B) Time-lapse images of a coculture between renal tubule epithelial (RTE) cells (mCherry or mCherry/GFP double positive) and HIV-1 infected macrophages (GFP only) demonstrate the elongation over time (black arrows) of a thin thread of membrane from an infected to an uninfected RTE cell. A similar elongated structure can also be appreciated in the HIV-1 infected macrophage present in the lower half of the images.

In addition to the formation of virological synapses, other cellular connections may also be involved in cell-to-cell viral transfer in the kidney. Tunneling NanoTubes (TNT) have recently emerged as another method by which HIV is spread for both T cells and macrophages [60–63]. TNT are reported to be responsible for a significant portion of infection in macrophage monocultures [60] and have been shown to directly facilitate the movement of viral particles between cells [64]. RTE cells form TNT as a means of intercellular communication through the exchange of cytoplasmic material [65], therefore it is possible that viral particles could be transferred between cells through this route. Indeed, cellular structures reminiscent of TNT were observed by live imaging in co-cultures between HIV infected macrophages and RTE cells (Figure 2B) [57]. Additional studies are required to understand the implications of those observations in HIV infection and dissemination in the kidney.

The different fates of HIV infected renal epithelial cells.

The link between HIV infection of kidney cells and renal disease was first demonstrated in a transgenic mouse model, in which the expression of HIV genes in renal cells recapitulated HIVAN pathology [66, 67]. Subsequent studies demonstrated that expression of individual viral genes was sufficient to induce pathogenic changes in renal cells [68]. Expression of HIV-Nef resulted in aberrant podocyte proliferation [69] and dedifferentiation [70] while expression of HIV-Vpr induced apoptosis, polyploidy and hypertrophy [6, 7]. These two viral proteins are sufficient to induce tissue damage, and they appear to work synergistically when co-expressed in the same cell, leading to more severe nephropathy [71].

In addition to abnormal pathogenic cellular phenotypes, a recent study from our group demonstrated that HIV infected RTE cells can undergo multiple rounds of proliferation [57], providing an additional mechanism by which HIV infection may persist and expand within the kidney, similarly to what has been demonstrated for other cell types [72]. Finally, transcriptional silencing, consistent with HIV latency, has also been observed in infected RTE cells [57], which can be partially reversed following treatment with latency reversing agents (unpublished data). Additional studies are needed to understand the cellular and virological mechanisms dictating each of the fates observed in HIV-infected renal cells to further our knowledge of HIV persistence and to inform the design of cure strategies (Figure 3).

Figure 3. Mechanisms and consequences of HIV-1 infection of the kidney.

Figure 3.

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(1) HIV infection of renal tubule epithelial (RTE) cells is initiated by cell-cell interaction with HIV-infected CD4+ T cells or macrophages infiltrating the kidney. Once infected, RTE cells perpetuate the infection cycle by transferring the virus back to CD4+T cells and macrophages coming into contact, and by producing viral particles that are then released in urine (2). Four cellular fates have been observed for HIV-infected RTE, including proliferation, hypertrophy, latency and cell death. (3) In the setting of HIV- to HIV+ kidney transplantation, the kidney allograft can be infected by the recipient strain despite ART treatment, suggesting a lymphocyte/macrophage cell-to-cell mediated infection. (4) In the setting of HIV+ to HIV+ kidney transplantation, the donor viral strain harbored in the allograft kidney is transferred to the recipient and is detected both as cell-free and cell-associated virus in the urine of the recipient post-transplantation.

Treatment considerations

Because of the established role of HIV infection in promoting HIVAN, and likely other forms of kidney disease, ART is considered first-line therapy for kidney disease in PLWH. At the same time, some antiretroviral drugs, especially tenofovir disoproxil fumarate (TDF) and some ritonavir-boosted protease inhibitors (PI/rs), have been associated with increased risk of CKD [73]. In contrast, a recent report demonstrated that another protease inhibitor, darunavir, may provide protection against HIV-induced kidney injury, likely through non-antiretroviral mechanisms [74]. In addition to the potential for some agents to cause kidney injury, newly licensed antiretroviral drugs (dolutegravir, raltegravir, elvitegravir, and cobicistat) interfere with the tubular secretion of creatinine and complicate the interpretation of kidney function estimates without evidence of significant nephrotoxicity [75].

The immediate initiation of ART in all individuals with diagnosed HIV infection, as recommended by current treatment guidelines, has been associated with an early improvement in kidney function [76]. Whether the renal benefits of early ART will be sustained with prolonged cumulative exposure to ART is unknown. The impact of switching from TDF to the newer prodrug tenofovir alafenamide on hard clinical outcomes is also an area for further study.

Conclusion

Despite improvements in mortality, PLWH, particularly in those of African American descent, remain at increased risk for kidney disease. Racial disparities in kidney disease prevalence are partially explained by variants in the APOL1 gene, although additional research is needed to better understand the impact of other factors. For PLWH who progress to ESRD, kidney transplantation from HIV+ donors has increased the donor pool for this population, offering an alternative to long-term dialysis. However the long-term implication of the potential presence of two separate viral strains in those recipients requires further study. Additional studies are also needed to understand the mechanisms and implications of HIV persistence in the kidney.

Acknowledgments

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants number P01DK056492 and R01DK108367.

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