HIV Compartmentalization in Male Genital Tract: Relevance for Viral Eradication : Infectious Diseases & Immunity

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HIV Compartmentalization in Male Genital Tract: Relevance for Viral Eradication

Peng, Xiaorong1,2,3; Isnard, Stéphane1,2,4; Lin, John1,2; Fombuena, Brandon1,2; Royston, Lena1,2; Routy, Jean-Pierre1,2,5,∗

Editor(s): Wang, Haijuan; Zhao, Wei

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Infectious Diseases & Immunity 1(2):p 86-92, July 2021. | DOI: 10.1097/ID9.0000000000000012
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A signature of human immunodeficiency virus (HIV) infection is the persistence of virus in cells and tissues despite antiretroviral therapy (ART) suppression of plasma HIV RNA levels below the limit of detection. Anatomical or cellular sites of HIV persistence are called viral reservoirs, which harbor potentially infectious virus for long periods of time and contribute to the rebounding virus upon ART interruption.[1] Furthermore, distinct HIV nucleotide sequences are present within various anatomical locations and tissues from the same individual, which was termed compartmentalization. These sequences encode HIV proteins associated with a wide range of virion cellular tropism, co-receptor utilization for viral entry and cytopathic effect.[2] Thus, identifying the properties of viral variants and their divergent evolution in different reservoirs is an important step in developing tissue-targeted treatment strategies to eradicate HIV.

The male genital tract (MGT) is one such reservoir with a unique environment for viral evolution. The MGT is composed of a series of organs: testis, epididymis, vas deferens, seminal vesicles, prostate, Cowper gland, ejaculatory ducts, urethra, Littré glands and penis. The MGT can be infected by many viruses and serves as a reservoir for several of them such as Zika, Ebola and HIV.[3] Persistence of HIV in semen has been well established to occur even in a subset of individuals displaying undetectable viremia under effective ART.[4,5] Testes represent a distinctive tissue having an immune-privileged status with an anatomic barrier as well as a pharmacologic sanctuary which limits antiretroviral drug penetration.[6–8] Specific tissue micro-environments such as the highly plastic tissue macrophages may play key roles in the establishment and reactivation of latently infected cells and the persistence of infected long-lived drug-resistant cells.[3,9]

However, studying such anatomical HIV sanctuaries is limited by the difficulty of obtaining tissues from well-defined study participants and the lack of a consistent assay for reliably assessing persistent HIV in tissues. Important information was provided by the “last gift” research from deceased people living with HIV (PLWH) after secondary disease,[10–12] by tissue donation following medical assistance in death or by tissue donation following gender reassignment surgery.[6,8,9,13–15] The non-human primate model is the only mean for parallel assessment of semen and all male genital organs to study viral persistence and compartmentalization.

Herein, we reviewed the recent work assessing sequence diversity and compartmentalization of HIV in MGT.

Reservoir size in MGT

The relative contribution of the MGT as a HIV reservoir has been addressed with different techniques assessing the size of HIV reservoirs detecting proviral DNA, intact provirus, viral RNA or protein production.[16] However, measurements of a single compartment could not provide a full picture of the MGT reservoirs.

The most accessible and well-studied sample of MGT is semen which is composed of cells and seminal fluid arising from the testis, epididymis, seminal vesicles, prostate, and mucus-secreting Cowper and Littré glands. HIV has been detected in semen as free viral particles and in infected cells.[17] In acutely-infected individuals, semen is very infectious and displays high HIV RNA and DNA levels in leukocytes.[18] The frequency of individuals with HIV proviral DNA in seminal leukocytes ranges from 21% to 75%.[18] Roughly 0.2% of CD4+ T cells and macrophages are infected in semen of ART-naïve PLWH.[18] During the chronic stage of the infection, seminal viral loads decreased in comparison to acute infection.[19] HIV RNA can also be detected in the semen of individuals with undetectable or very low blood viral load, and also in HIV controllers with levels positively associated with those measured in blood plasma.[20–24] Although ART rapidly reduces blood and seminal viral loads in a majority of PLWH, low but detectable numbers of virions and infected cells persisted in their semen in a substantial group of individuals (range, 4%–48%) for months to years.[21–24] However, there are exceptions, with intermittently high seminal viral loads reported in some virally suppressed PLWH from months to years.[25] Nevertheless, the residual level of virions or infected cells in semen of treated PLWHs are generally low and not sufficient to lead to secondary HIV transmission.[4] Indeed, a multicentre, prospective, observational study revealed that risk of HIV transmission through condomless sex in serodifferent couples of men who have sex with men (MSM) with the HIV-positive partner taking ART is effectively zero (upper 95% CI 0.23 per 100 couple-years of follow-up).[26]

Studies on the HIV reservoirs in organs of MGT are very limited. Using testes obtained from individuals who underwent elective gender-affirming surgery, we measured total and integrated HIV DNA in total testis from six individuals on suppressive ART. Total HIV DNA ranged from 0.8 to 198 copies per million cells in the right testis from six participants and ranged from 2 to 39 copies per million cells in the left testis of four individuals for whom HIV DNA was detectable.[13] Another study performed in deceased participants with low or undetectable plasma viral load assessed HIV DNA levels in testis and found 268 to 577,778 copies/106 cells (n = 10).[27] Ganor et al. found that the mean integrated HIV DNA copy number of 1 × 103 was detected in 106 total urethral cells using penile tissues from HIV-infected individuals under ART.[28] HIV DNA was enriched in sorted CD68+ macrophages (approximately 1.7 × 104 copies per 106 cells) compared to total urethral cells (0.4 × 103 copies per 106 cells).[28] However, integrated HIV DNA could not be detected in 100,000 to 180,000 sorted CD3+ T cells in penile urethral tissue.[28]

One observational study evaluated six HIV-infected individuals, four with viral suppression during ART and two with rebound viremia after stopping ART, who accepted to provide serial blood samples before death and their bodies after death for rapid autopsy. HIV reservoirs were measured by digital droplet PCR quantifying HIV DNA levels in prostate, testis and seminal vesicle: 10 to 50 copies/106 cells were detected in all three organs.[10]

In summary, different techniques (PCR, in situ hybridization, outgrowth assays) allowed the detection of HIV in most MGT organs, including in ART-treated PLWH, indicating that the MGT host HIV latent reservoirs that could puzzle HIV eradication strategies. In addition, sequencing of HIV genome allowed compartmentalization studies.

The compartmentalization in MGT

Viral compartmentalization is the indication of restricted gene flow between different anatomic compartments, which can result in genetically distinct HIV sequences in tissues or cell types. Multiple studies have shown that semen from a subset of patients harbors compartmentalized strains.[4,14,29–39] A summary of genetic compartmentalization studies on HIV strains between MGT organs and blood is shown in Table 1. Local viral replication can result in compartmentalized population, which is thought to be the primary mechanism for the compartmentalization in MGT organs.[32,40] When the viral replication was suppressed by ART, clonal amplification could also alter the composition of the viral population in MGT.[32] Other mechanisms leading to detection of compartmentalization are discussed here as well.

Table 1 - Summary of genetic compartmentalization studies on HIV strains between MGT and blood
Infection stage No. of patients with differences between different samples (positive/analyzed) Samples Sequencing method Assessment of viral compartmentalization Amplicon PMID
Early Infection 1/6 SP vs. BP HTA Quantitative phosphorimager analysis env V1-V2 15452240
Early Infection 2/6 SP vs. BP Roche 454 FLX titanium platform Slatkin-Maddison and Fst env C2-V3 27548440
Chronic Infection 4/6 SP vs. BP Single-genome amplification Fst env C2-V3 20371483
Chronic Infection 5/5 SP vs. SC pGEM-T easy cloning system Slatkin-Maddison and Fst env C2-V5 12487815
Chronic Infection At least 6/24 SP vs. BP Primer ID deep sequencing Slatkin-Maddison test V1/V3 32269129
Chronic Infection 10/10 SP vs. BP Illumina MiSeq with a Primer ID approach Slatkin-Maddison and Fst C3-V5 32269124
Chronic Infection 7/7 SP vs. BP TOPO TA cloning system Slatkin-Maddison and Fst C2-V5 20231027
Chronic Infection 2/8 SP vs. BP Single-genome amplification Slatkin-Maddison and Fst gp160 30996101
Chronic Infection 7/14 SP vs. BP TOPO TA cloning system Slatkin-Maddison and Fst env C2-V3 22997072
Chronic Infection 3/5 SP vs. BP MiSeq Illumina Slatkin-Maddison and Fst env (C2-V3), gag (p24), and pol 32434884
ART or Chronic (Viral load >200) 4/5 Blood vs. genitourinary sites TOPO TA cloning system the number of migration events C2-V5 18426336
ART 6/10 PBMC vs. testes Single-genome amplification Slatkin-Maddison and Fst nef region 31189714
ART 3/6 SP vs. BP PCR Drug resistant variants transcriptase (RT) and protease 9814860
MGT: Male genital tract; ART: Antiretroviral therapy; SP: Seminal plasma; BP: Blood plasma; SC: Seminal cells; PBMC: Peripheral blood mononuclear cells; HTA: Heteroduplex tracking assay; PCR: Polymerase chain reaction; Fst: F-statistic; PMID: PubMed unique identifier.

Compartmentalization in semen during HIV infection

During early HIV infection, several studies showed evidence of compartmentalization between blood and seminal plasma. Chaillon et al. longitudinally collected plasma and seminal fluid samples during primary HIV infection in six antiretroviral-naïve MSM. They detected evidence of viral compartmentalization between the blood and seminal compartments in two out of six participants. Interestingly, both individuals lost compartmentalization at later time points, 182 and 457 days post infection.[29] Another study in MSM collected paired samples of blood and semen from seven individuals with early HIV-infection: a greater HIV genetic diversity in seminal plasma was observed than in blood plasma.[41] At a median of five weeks after infection, Ritola et al. showed evidence for compartmentalization between blood and seminal plasma in one out of six untreated subjects.[30]

During chronic HIV infection, genetic compartmentalization between virus strains present in blood and semen has been observed in 61% of the 142 PLWH analyzed in 13 independent studies, showing higher frequency of compartmentalization compared to the acute phase.[4,40] Using high throughput sequencing of the V1/V3 region of the HIV envelope gene, varying degrees of compartmentalization were observed in different studies, ranging from near-complete separation of blood and semen-derived sequences, to minor compartmentalization in 6/24 (25%) paired blood and semen samples from 24 ART-naïve men.[31] Kariuki et al. found evidence of compartmentalization in ten ART-naive men using a similar approach. When sequenced to a lower depth, compartmentalization was found in only about 50% of the study participants.[32] In HIV clade C infection, HIV sequences from four body compartments (seminal plasma, seminal cells, blood plasma, blood cells) indicated significant phylogenetic compartmentalization (P < 0.0001) in all seven chronically infected patients.[33,34]

Using an ultrasensitive in situ hybridization assay, higher levels of HIV mRNA were consistently detected in seminal mononuclear cells as compared to PBMC in PLWH up to 5 years after initiating ART, possibly explained by a different evolution of Envelope populations in blood and semen.[37] There were two patterns of viral sequence relationship between blood and seminal plasma: a clustering of sequences from blood and semen or distinct clusters in the two compartments on ART.[38,39]

Compartmentalization in MGT organs during HIV infection

Virus subpopulations in MGT organs divergent from blood were observed in chronically infected PLWH.[35,36] Diem et al. collected blood plasma, PBMC, urine, urethral swabs, seminal plasma, and biopsies from urethra, prostate gland, and rectum at the same time from five individuals. Three of them demonstrated compartmentalization of blood plasma versus urogenital tract.[36]

The subgenomic nef gene in testes was characterized by single genome amplification in 10 individuals on suppressive ART after gender reassignment surgery. When all intact nef sequences were evaluated, 60% of participants displayed significant genetic compartmentalization between blood and testis, but none did so when the evaluation was restricted to unique sequences per site.[14] More studies are needed to investigate the characteristic of viral reservoir in MGT organ. HIV DNA and compartmentalization in different MGT organs are summarized in Figure 1.

Figure 1:
The detection of HIV DNA and compartmentalization in different MGT organs. HIV: Human immunodeficiency virus; MGT: Male genital tract; Y: Yes (confirmed by studies); ND: No study did such test; PBMC: Peripheral blood mononuclear cell; ART: Antiretroviral therapy.

Although compartmentalization in the MGT was frequently studied between blood and semen in acutely and chronically infected PLWH, studies assessing compartmentalization on ART and the contribution of different MGT organs were limited. HIV compartmentalization has been well documented in the semen but only few studies assess compartmentalization in MGT organs due to difficult access. Clinical studies about novel therapies to eradicate the virus in MGT are needed.

Mechanisms of compartmentalization in MGT

Although there are few studies focusing on HIV in the MGT during acute HIV infection, they showed a lower percent of participants with compartmentalization during this phase.[29,30] Early spread of the virus is predominantly observed from blood to the MGT, with consequent establishment of a local viral population.[29] Indeed, phylogenetic trees of HIV sequences were rooted in blood, suggesting that the viral sequences in MGT are seeded by incoming variants from the blood.[31,32]

Routes of transmission

Moreover, different routes of transmission are associated with divergent virus evolution subsequently leading to possible compartmentalization. Heterosexual transmissions are mostly related to a single founder virus.[42] When only one founding virus is transmitted, the viral population is initially homogenous and then diversifies as it escapes to a new host immune pressure. However, in MSM or intravenous drug users (IVDU), multiple founding viruses are not uncommon.[43] Foreskin Langerhans cells and urethral macrophages were identified as a major portal of entry for HIV.[11] Since infection in MSM have been described through a rectal or penile route, it would be interesting to assess how these two distinct routes may affect strain diversity in PLWH or animal models.

Immune privileged organs

Localized sustained replication can occur in the MGT of chronically infected PLWH [4,31,32] and specific strains can be amplified by cellular proliferation.[4,31,32] Moreover, the virus could continue to encounter varied selective pressure during this chronic stage, participating in the observed compartmentalization in the MGT.

MGT organs have specific immune features. Testes are immune privileged organs, like the eyes and brain. Such organs are protected by an anatomic barrier and have several mechanisms of immune tolerance to prevent edema or swelling during inflammation.[3,8] Macrophages are the largest population of immune cells in the testis and displays relatively low inflammatory responses and high immunosuppressive properties compared with macrophages in others tissues.[44] Moreover, immunosuppressive purinergic signaling has been detected in human testicular Tregs and memory CD8+ T cells.[13]

The epididymis shows a distinctive mixture of immune features. Regions near to the testes present with a tolerogenic-orientated environment, while regions far away from testis turned to a classical systemic immunity. This phenomenon is caused by different expression of some immunoregulatory genes, including indoleamine 2,3-dioxygenase, activin A and different pattern recognition receptors.[45]

Hence, local immune tolerance or inflammatory features of MGT organs can play a role in the establishment and evolution of HIV reservoir by increasing cell seeding, enhancing replication and/or preventing elimination of infected cells by the immune system. The global impact of local immune mechanisms on HIV evolution in these organs needs further investigations.

ART agents distribution in MGT

ART can efficiently suppress HIV replication in blood. However, ART distribution in tissues is dependent on molecular weight, lipophilicity, drug binding protein, and is also influenced by a dynamic interplay between membrane drug uptake/efflux and cellular metabolic dynamics. Penetration varies by drug (as opposed to class) and was shown to be highly variable between individuals.[46]

Our ART quantification studies in the testicular tissues in PLWH have shown that nucleoside analogues, including emtricitabine, lamivudine, and tenofovir, penetrated effectively into testis while their phosphorylated metabolites displayed relatively lower concentration in this tissue compared to blood. Plasma concentrations of two protease inhibitors, ritonavir and atazanavir, were not different in blood and testis reaching an effective therapeutic concentration.[6,7,46] Moreover, we showed minor differences in the expression of drug-efflux pump expression in testis T cells compared to their blood counterparts, with reduced expression of multidrug resistance-associated protein 1 (MRP1). However, no difference in the expression of permeability-glycoprotein (p-gp), breast cancer resistance protein (BRCP), metabolic enzymes CYP3A4 nor UGT1A1 was observed.[15]

Inadequate drug concentration and different expression of drug-efflux pump in MGT may create a favorable environment for the stochastic emergence of resistant mutants upon viral replication in PLWH on ART. The evolution of resistance mutations in blood and semen were frequently discordant, which suggested the virus in MGT is at least partly produced locally and may be under different drug selective pressures than virus in blood.[38] Moreover, transmitted drug-resistant HIV can persist longer in semen than in blood and may contribute to the secondary transmission of drug resistance.[47]

Local inflammation

The presence of a sexually transmitted infection (STI) is associated with greater multiplicity of initial HIV infection. STIs and local inflammation may enhance clonal expansion of HIV-infected cells and promote residual replication on ART. Due to consistent CMV antigen stimulation, CMV-specific CD4+ T cells persist abundantly and functionally during HIV infection.[48] Whether seminal shedding of HIV is associated with seminal CMV shedding is still under debate. A case-control analysis by Gantner et al. showed that HIV RNA levels in seminal plasma did not correlate with CMV DNA, among virologically suppressed MSM.[5] However, Gianella et al. showed that seminal HIV was associated with CMV shedding in ART-treated HIV-infected MSM.[49]

In uninfected men, the epididymis, seminal vesicles, and prostate naturally encompass resident macrophages, and to a lesser extent CD4+ T cells. However, the prostate is frequently inflammatory (eg, in case of benign prostate hyperplasia or STIs) and often displays immune infiltrates mostly composed of activated memory CD4+ T cells.[12] Then, local inflammation may explain the higher frequency of infected cells in the prostate and seminal vesicles.

No studies assessed the association between local inflammation and compartmentalization in MGT on ART yet. However, in six primary HIV-infected people, no association between local inflammation and viral trafficking between semen and blood was observed.[29] Another group found that there was no different prevalence of compartmentalization in semen in men with or without STI-associated urethritis, and that viral populations in semen were largely stable during STI treatment.[31] Furthermore, inflammation of MGT organs was found to have no relation with viral compartmentalization or shedding in semen in chronically-infected macaques.[50] These findings support that STI-related inflammation has no or limited influence on the formation of compartmentalized lineages in the MGT. Whether local inflammation in different MGT organs plays a role in HIV compartmentalization requires further assessment.

Clonal expansion

One mechanism that maintains the HIV reservoir under suppressive ART is the persistence and proliferation of cells infected before the initiation of ART.[1] Over 50% of latent reservoirs are maintained through clonal expansion in PBMC under suppressive ART.[31,32] The source of residual viremia in patients on ART may be through the release of virus from the clonally expanded CD4+ T cells. Due to the high-fidelity cellular DNA polymerase, the proliferation of HIV-infected cells produces identical proviral sequence copies. The proliferation of latently HIV-infected cells can differ substantially between blood and tissues, including testes.[14] However, the degree of clonal amplification was not obviously associated with the extent of compartmentalization between semen and blood.[33]

Clonal amplification and sustained replication in MGT could alter the composition of the viral population in MGT relative to that in the blood, which could result in the compartmentalization of HIV population in MGT.

Potential strategies to reduce viral reservoir size in MGT

Based on the lessons from the compartmentalization, several strategies to reduce the viral reservoir in MGT can be explored. ART was the first treatment showing promise in preventing further seeding of HIV reservoirs in MGT organs and preventing replication in deep tissues. ART agents with efficient penetration into MGT should be selected, started as soon as possible after diagnosis to reduce HIV reservoir size. Moreover, new methods to deliver ART agents to MGT organs should be studied to increase the tissue drug concentration. It is recommended that CMV and other STI disease should be treated immediately to reduce the inflammation in MGT. The impact of new therapeutic strategies such as neutralizing antibodies that are currently tested should be also assessed in MGT organs.


Though MGT remains difficult to study in humans, these organs are critical in better understanding secondary HIV transmission and characterizing potential HIV cure strategies. In this review, we discussed the heterogeneity of reservoirs in MGT organs and the mechanisms that could be involved in tissue compartmentalization, including differential immune pressures, inflammation, clonal expansion of different cell types, and local concentrations of antiviral drugs. ART was shown to abrogate HIV transmission despite low level viral shedding in seminal fluid and to reduce HIV reservoir seeding when started early after diagnosis. Finally, improved access to MGT tissues in deceased individuals, persons under gender affirmation surgeries and new strategies targeting HIV reservoir in the MGT could guide new directions for viral eradication.


We are highly grateful to Angie Massicotte, Josée Girouard, and Cezar Iovi for coordination and assistance.


This work was funded by the China Scholarship Council (No. 201906325018), the Canadian Institutes of Health Research (CIHR; grants MOP 103230 and PTJ 166049), the Vaccines & Immunotherapy Core of the CIHR Canadian HIV Trials Network (CTN, grant CTN 257), the CIHR-funded Canadian HIV Cure Enterprise (CanCURE) Team Grant HB2-164064. This work was also supported by the Fonds de la Recherche Québec-Santé (FRQ-S): Réseau SIDA/Maladies infectieuses and Thérapie cellulaire. Stéphane Isnard is supported by a Fond de Recherche Québec Santé fellowship and a CIHR/CTN Postdoctoral Fellowship Award. Jean-Pierre Routy is the holder of the Louis Lowenstein Chair in Hematology and Oncology, McGill University and William Turner award holder from the McGill University Health Centre.

Author Contributions

Xiaorong Peng wrote the first draft of the manuscript. Stéphane Isnard, John Lin, Brandon Fombuena and Lena Royston provided critical revision of the manuscript. Jean-Pierre Routy conceived and designed the manuscript. All authors approved the final version for publication.

Conflicts of Interest



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HIV; Compartmentalization; Male genital tract; Reservoir; Testes

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