Seminal Human Immunodeficiency Virus Research Articles

Cytokine Network and Sexual Human Immunodeficiency Virus Transmission in Men Who Have Sex With Men.

Seminal human immunodeficiency virus (HIV) transmission from men to their partners remains the main driver of HIV epidemics worldwide. Semen is not merely a carrier of the virus, but also provides an immunological milieu that affects HIV transmission. We collected blood and semen from people with HIV whose epidemiologically linked sexual partners either did or did not acquire HIV. Viral transmission was confirmed by phylogenetic linkage (HIV pol). We measured the concentration of 34 cytokines/chemokines by Luminex in the blood and semen of 21 source partners who transmitted HIV (transmitters) and 22 who did not transmit HIV (nontransmitters) to their sexual partners. Differences between cytokine profiles in transmitters versus nontransmitters were analyzed using the multivariate statistical technique of partial least square discriminant analysis. The cytokine profile in seminal fluid, but not in peripheral blood, was significantly different between men who have sex with men (MSM) who transmitted HIV and those who did not transmit HIV to their sexual partners (E = 19.77; P < .01). This difference persisted after excluding people with undetectable HIV RNA levels in nontransmitters. Seminal cytokine profiles correlated with transmission or nontransmission of HIV from the infected MSM to their partners, independently from seminal viral load. Seminal cytokine spectra might be a contributing determinant of sexual HIV transmission, thus providing new directions for the development of strategies aimed at preventing HIV transmission.

Longitudinal Viral Dynamics in Semen During Early HIV Infection.

Multiple viruses coinfect the male genital tract, influencing each other’s replication and perhaps affecting human immunodeficiency virus (HIV) pathogenesis and disease progression. This study included 453 longitudinal seminal samples from 195 HIV-infected men from the San Diego Primary Infection Resource Consortium and 67 seminal samples from HIV-negative healthy controls. Seminal HIV RNA and DNA from 7 human herpesviruses (HHVs) were measured by real-time polymerase chain reaction. Longitudinal shedding rates were determined by Kaplan-Meier survival analysis. Predictors of viral shedding were determined using backwards selection in a multivariable generalized estimating equation model. HIV-infected participants presented significantly increased rates of seminal HHV shedding compared with HIV-uninfected controls. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) were the most commonly detected HHV in semen of HIV-infected participants. Persistent shedding was more common for CMV and EBV when compared to other HHVs. With exception of HHV-7, HHV shedding was not significantly influenced by HIV RNA levels, CD4+ cell counts, or antiretroviral therapy. Presence of CMV, EBV, and herpes simplex virus (HSV) were independent predictors of genital HIV RNA shedding after adjusting for plasma HIV RNA and longitudinal measurements. Seminal replication of multiple HHVs is common in our HIV primary infection cohort. Genital replication of CMV and EBV was the most common and was significantly associated with seminal HIV RNA shedding. Prevalence of HSV shedding was lower and mostly intermittent, but its association with seminal HIV RNA was the strongest. Understanding the complex viral milieu in semen is important for HIV transmission but might also play a role in HIV pathogenesis and disease progression.

Seminal Human Immunodeficiency Virus Blips and Structured Natural Conception In Serodiscordant Couples

TO THE EDITOR—As the prognosis for human immunodeficiency virus (HIV)– infected patients has improved with effective therapies, the prospect of raising children has become a realistic expectation among many serodiscordant couples. For seronegative women, structured natural conception can offer an appealing (and affordable) balance between getting pregnant and avoiding infection from their seropositive male partner. However, despite sustained long-term suppression of plasma viremia by antiretroviral therapy below the level of detection, some HIV-infected men intermittently and unpredictably have detectable free or cell-associated HIV in their semen, independent of drug regimen or seminal drug levels [1–4]. Shedding has been associated with transient increases in T-cell activation confined to the male genital tract [4–6]. The finite (albeit quite small) possibility of infecting a seronegative partner during intercourse even when the seropositive patient has plasma virus fully suppressed looms over structured natural conception initiatives for discordant heterosexual couples wanting offspring [1, 7, 8]. Unfortunately, an absolute zero risk for a coital act seems theoretically unattainable, given the limitations of current interventions, since elimination of cellassociated HIV is not yet achievable [9]. Integrated proviral DNA lies dormant in compartmentalized cellular reservoirs, prominently including the neurological and genitourinary compartments. When HIV-harboring cells within a compartment are stimulated, site-specific viral blips occur irrespective of systemic events in blood and elsewhere. Restricted by their specific mechanism of action, drugs targeting isolated intracellular steps in the preintegration viral life cycle cannot interfere with release of virus during the first ensuing cycle after activation [10]. Even when pregnancy is the goal, unprotected intercourse should be avoided in the presence of recognized sexually transmitted diseases or other genitourinary infections; however, self-limited productive HIV infection is likely more often triggered by subclinical and, thus, unsuspected inflammation (such as asymptomatic shedding of herpesviruses) [5, 6, 11, 12]. The very small residual risk of HIV transmission associated with structured natural conception may be acceptable to qualifying and well-informed couples (especially when other options are unavailable or impractical), but the ultimate decision maker must always be the unharassed female partner [13–15].

Shedding of HIV and Human Herpesviruses in the Semen of Effectively Treated HIV-1–Infected Men Who Have Sex With Men

Current antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) in blood to undetectable levels in most infected individuals; however, some men shed HIV in semen despite suppressed levels in blood. This study included 114 chronically HIV type 1-infected men who have sex with men, who were receiving ART with blood plasma HIV <500 copies/mL. Asymptomatic participants were screened for bacterial sexually transmitted infections (STIs) and nonspecific genital inflammation. Levels of HIV and 7 human herpesviruses were measured by real-time polymerase chain reaction in seminal plasma. Predictors of HIV seminal shedding were determined for the entire cohort, and on the subset of 100 subjects with blood plasma HIV <50 copies/mL. Eleven subjects (9.6%) had detectable levels of seminal HIV (median, 2.1 log10 copies/mL), and 72 (63.2%) had at least 1 herpesvirus detected in their seminal plasma. Detectable levels of seminal HIV were present more often in persons with plasma HIV between 50 and 500 copies/mL compared to those <50 copies/mL (P values adjusted for false discovery rate [FDR] = 0.08). There was a trend for high-level cytomegalovirus (CMV; >4 log10 DNA copies/mL; FDR-adjusted P = .08), and presence of Epstein-Barr virus (FDR-adjusted P = .06) in semen to be associated with detectable seminal HIV levels. In a subanalysis of 100 subjects with blood plasma HIV <50 copies/mL, high levels of CMV in semen was the only significant predictor for seminal HIV shedding. Low-level HIV replication in blood and high-level seminal CMV shedding, but not presence of asymptomatic STIs, is associated with seminal shedding of HIV in men receiving ART, conferring a potential risk for HIV transmission.

Generalizing Evidence From Randomized Clinical Trials to Target Populations: The ACTG 320 Trial

Properly planned and conducted randomized clinical trials remain susceptible to a lack of external validity. The authors illustrate a model-based method to standardize observed trial results to a specified target population using a seminal human immunodeficiency virus (HIV) treatment trial, and they provide Monte Carlo simulation evidence supporting the method. The example trial enrolled 1,156 HIV-infected adult men and women in the United States in 1996, randomly assigned 577 to a highly active antiretroviral therapy and 579 to a largely ineffective combination therapy, and followed participants for 52 weeks. The target population was US people infected with HIV in 2006, as estimated by the Centers for Disease Control and Prevention. Results from the trial apply, albeit muted by 12%, to the target population, under the assumption that the authors have measured and correctly modeled the determinants of selection that reflect heterogeneity in the treatment effect. In simulations with a heterogeneous treatment effect, a conventional intent-to-treat estimate was biased with poor confidence limit coverage, but the proposed estimate was largely unbiased with appropriate confidence limit coverage. The proposed method standardizes observed trial results to a specified target population and thereby provides information regarding the generalizability of trial results.

Seminal plasma HIV levels in men with asymptomatic sexually transmitted infections

The effect of asymptomatic sexually transmitted urethral infections on human immunodeficiency virus (HIV) RNA viral load in semen is poorly defined. We studied five such patients. Those on antiretrovirals (n = 2) had lower seminal plasma viral loads (SPVL) (2.11 and 1.98 log(10) copies/mL) than those not on antiretrovirals (n = 3) (2.27-3.78 log(10) copies/mL). One patient who was not taking antiretrovirals had a 94% decline in SPVL after treatment of asymptomatic Chlamydia trachomatis urethritis, suggesting that asymptomatic infection may be a co-factor for HIV transmission.

Susceptibility of Human Testis to Human Immunodeficiency Virus-1 Infection in Situ and in Vitro

Semen represents the main vector for human immunodeficiency virus (HIV) dissemination worldwide and has been shown to harbor replication-competent virus despite otherwise effective highly active anti-retroviral therapy, which achieves undetectable viral load in plasma. Despite this, the origin of seminal HIV particles remains unclear, as does the question of whether the male genital tract organs contribute virus to semen. Here we investigated the presence of HIV receptors within the human testis using immunohistochemistry and quantitative real-time polymerase chain reaction. We also analyzed the infectivity of a dual tropic HIV-1 strain in an organotypic culture, as well as the impact of viral exposure on testosterone production. Our study establishes that CXCR4+, CCR5+, CD4+, and DC-SIGN+ cells are present within the interstitial tissue of human testis and that these molecules persist throughout our organotypic culture. Our data also reveal that the human testis is permissive to HIV-1 and supports productive infection, leaving testosterone production apparently unaffected. Infected cells appeared to be testicular macrophages located within the interstitial tissue. That the testis itself represents a potential source of virus in semen could play a role in preventing viral eradication from semen because this organ constitutes a pharmacological sanctuary for many current antiretrovirals.

Snapshots for May 2006

Snapshots for May 2006

Limited Penetration of Lopinavir and Ritonavir in the Genital Tract of Men Infected with HIV-1 in Brazil

The concentrations of lopinavir and ritonavir in seminal and blood plasma and the seminal human immunodeficiency virus (HIV) viral load were quantified by HPLC and the Nuclisens assay, respectively, in a cross-sectional study of 16 HIV-1-infected Brazilian men under stable treatment with a lopinavir/ritonavir containing antiretroviral regimen. Semen and blood samples were collected on 2 occasions: at 6 to 60 minutes before ("trough"), and 5 to 6 hours after ("peak") ingestion of regular doses of lopinavir/ritonavir. Median seminal lopinavir levels were 120.6 ng/mL (range, <20-1481.8 ng/mL) and 233.1 ng/mL (range, 48.4-1133.4 ng/mL) at trough and peak points, respectively. The corresponding values for ritonavir were 9.2 ng/mL (range, <5-47 ng/mL) and 17.1 ng/mL (range, 6.6-66.7 ng/mL). The median concentrations of lopinavir and ritonavir in semen were, respectively, 1.9% to 3% and 3.7% to 4.4% of those measured in blood plasma samples collected within 30 minutes. HIV-1 viral load was detectable in the semen of 2 and in the blood of 6 of 16 patients. These results may have implications for drug-resistant HIV-1 evolution and transmission.

Higher Concentration of HIV RNA in Rectal Mucosa Secretions than in Blood and Seminal Plasma, among Men Who Have Sex with Men, Independent of Antiretroviral Therapy

High levels of human immunodeficiency virus (HIV) in rectal secretions and semen likely increase the risk of HIV transmission. HIV-infected men who have sex with men made 2-3 study visits, over 4 weeks, to assess rectal, seminal, and plasma levels of HIV RNA. Mixed-effects models estimated the effect of factors on HIV shedding. Twenty-seven (42%) of 64 men were receiving antiretroviral therapy (ART); regardless of ART use, median HIV RNA levels were higher in rectal secretions (4.96 log(10) copies/mL) than in blood plasma (4.24 log(10) copies/mL) or seminal plasma (3.55 log(10) copies/mL; P<.05, each comparison). ART was associated with a 1.3-log(10) reduction in rectal HIV RNA in a model without plasma HIV RNA; with and without plasma RNA in models, ART accounted for a >1-log(10) decrease in seminal HIV RNA levels. Thus, controlling for plasma HIV RNA, ART had an independent effect on seminal, but not rectal, HIV levels.

Persistence of human immunodeficiency virus in semen after adding indinavir to combination antiretroviral therapy.

Changes in human immunodeficiency virus (HIV) type 1 concentration and protease genotype were evaluated in semen specimens from 22 HIV-positive men before and 6 months after the addition of indinavir to dual nucleoside therapy. Seminal HIV was detected by polymerase chain reaction analysis for DNA or RNA for 59% of men before combination treatment and persisted at 6 months for 31% of the men who initially had seminal HIV detected (P = .026). The maximum levels of cell-free RNA, cell-associated RNA, and proviral DNA in semen before treatment and at 6 months were 400,000 and 10,000 copies/mL, 70,000 and 27,000 copies/mL, and 80,000 and 3,000 copies/mL, respectively. Three of the four men with persistent seminal DNA had plasma viral loads of > 10,000 copies/mL before treatment. One patient who became intolerant to indinavir had seminal HIV RNA detected by PCR analysis after 6 months. Although none of the cultures of semen specimens from the four men with PCR analysis-detectable seminal DNA after 6 months yielded HIV, indinavir resistance mutations were identified in a seminal leukocyte DNA specimen from one patient, and a second patient whose therapy was switched to saquinavir had different protease inhibitor resistance mutations in seminal and blood leukocyte DNA specimens. HIV-1 protease inhibitor resistance mutants may emerge in the semen of patients receiving combination therapy.