Seth L. Welles

Quantitative proviral DNA and antibody levels in the natural history of HTLV-I infection

The pathogenesis of human T-cell lymphotropic virus type I (HTLV-I) in adult T-cell leukemia/lymphoma (ATL) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) is poorly understood. We prospectively followed up and evaluated the virologic correlates of infection in transfusion recipients after seroconversion, in asymptomatic carriers, and in ATL and HAM/TSP patients. Proviral DNA levels (copies/105 lymphocytes) were determined by real-time automated polymerase chain reaction and antibody titers by end-point dilution by use of an HTLV-I enzyme-linked immunoassay. In early infection, proviral load was initially elevated (median, 212 copies/105 lymphocytes at time 1) and later decreased (median, 99 copies at time 2, and 27 copies at time 3). Corresponding antibody titers were low at time 1 (1:2154), had significantly increased by time 2 (1:12312), and were stable by time 3 (1:4694). These viral markers were significantly lower in asymptomatic carriers than in HAM/TSP or ATL patients. Therefore, proviral load and antibody titers may be useful as predictive markers of disease among carriers.

HIV-1 genotypic zidovudine drug resistance and the risk of maternal-infant transmission in the women and infants transmission study.

ObjectivesAlthough the treatment of pregnant women and their infants with zidovudine (ZDV) has been remarkably effective in preventing the perinatal transmission of human HIV-1, many potentially preventable infections still occur. To examine whether the risk of perinatal infection is increased among women who carry ZDV-resistant HIV-1, the role of genotypic ZDV resistance in perinatal transmission was evaluated. MethodsThe reverse transcriptase (RT) region of clinical isolates from culture supernatants of 142 HIV-1-infected women enrolled in the Women and Infants Transmission Study (WITS), who had been treated with ZDV during pregnancy was sequenced. Results from genotypic sequencing were linked to demographic, laboratory, and obstetrical databases, and the magnitude of association of having consensus drug-resistant HIV-1 RT mutations with transmission was estimated. ResultsTwenty-five per cent (34/142) of maternal isolates had at least one ZDV-associated resistance mutation. A lower CD4 cell percentage and count (P  = 0.0001) and higher plasma HIV-1 RNA (P  = 0.006) were associated with having any ZDV resistance mutation at delivery. Having any RT resistance mutation [odds ratio (OR): 5.16; 95% confidence interval (CI): 1.40, 18.97; P  = 0 0.01], duration of ruptured membranes [OR: 1.13 (1.02, 1.26) per 4 h duration; P  = 0.02], and total lymphocyte count [OR: 1.06 (1.01, 1.10) per 50 cells higher level; P  = 0.009] were independently associated with transmission in multivariate analysis. ConclusionMaternal ZDV resistant virus was predictive of transmission, independent of viral load, in these mothers with moderately advanced HIV-1 disease, many of whom had been treated with ZDV before pregnancy.

Selective vertical transmission of HIV-1 antiretroviral resistance mutations

Objective:To examine the patterns of vertical transmission of zidovudine (ZDV) resistance mutations. Design:HIV-1 reverse transcriptase codons 10–250 were sequenced from 24 pairs of ZDV-exposed women and their HIV-infected infants as part of the Women and Infants Transmission Study. Methods:Viral RNA was extracted from tissue culture supernatants and sequenced using fluorescent dye-primer chemistry and an automated sequencer. Results:For 17 of these pairs, maternal and infant sequences were identical to one another and lacking known ZDV resistance mutations. The remaining seven maternal sequences contained known mutations associated with ZDV resistance at reverse transcriptase codons 70, 210, 215 and 219. In each case where the maternal HIV isolate showed a pure mutant species, the infant sequence was identical. When the maternal sequence showed the presence of a sequence mixture at codon 70 or 219, the infants virus showed only wild-type sequence even when the ZDV-resistant mutant was quantitatively dominant in the mother. The single maternal HIV isolate showing mixed sequence at codon positions 210 and 215 transmitted an unmixed mutant to the infant at both positions. When maternal mixtures were present at sites not associated with ZDV resistance, only the dominant species appeared in the infant. Conclusions:When maternal HIV isolates contained mixed wild-type and ZDV-resistant subpopulations, only a single component of the mixture could be detected in the infected infants. Resistance mutants without the codon 215 mutation were not transmitted from mixtures, even when the mutants formed the majority of circulating maternal virus. In perinatal HIV transmission, specific ZDV-resistant HIV genotypes circulating in the maternal virus pool may influence whether infection in the infant will be established by a wild-type or ZDV-resistant HIV strain.

History of childhood sexual abuse and HIV risk behaviors in homosexual and bisexual men

OBJECTIVES We examined the prevalence and frequency of childhood sexual abuse and their association with sexual risk among a sample of gay and bisexual men. Methods. Cross-sectional data were collected by survey from randomly selected gay and bisexual men who attended the 1997 and 1998 Minneapolis/St. Paul Gay, Lesbian, Bisexual, and Transgender Pride Festivals. Data included demographics, sexual activity, history of childhood sexual abuse, HIV status, history of sexually transmitted infection, use of sex-related drugs (such as crack, cocaine, Ecstasy, amyl nitrate, crystal methamphetamine, and Special K), and history of exchanging sex for payment. Results. childhood sexual abuse was reported by 15.5% of the survey respondents (n = 134). Those who reported experiencing abuse regularly were more likely to (1) be HIV positive, (2) have exchanged sex for payment, and (3) be a current user of sex-related drugs. Neither unsafe sex nor sexually transmitted infections were associated with childhood sexual abuse. CONCLUSIONS These findings show that more than 1 in 7 gay and bisexual men in a non-clinical, festival-based setting were victims of childhood sexual abuse and that childhood sexual abuse was associated with alarmingly high rates of men who were HIV infected and antecedent risk behaviors.

Highly active antiretroviral therapy does not completely suppress HIV in semen of sexually active HIV-infected men who have sex with men

Objective:Although HAART can suppress genital shedding and sexual transmission of HIV, men who have sex with men (MSM) have experienced a resurgent HIV epidemic in the HAART era. Many HIV-infected MSM continue to engage in unsafe sex, and sexually transmitted infections (STIs) or other factors may promote genital HIV shedding and transmission in this population despite HAART. In this study, we determined the prevalence of seminal HIV shedding in HIV-infected MSM on stable HAART, and its relationship with a number of clinical, behavioral and biological variables. Design:Sexually active HIV-infected men using HAART were recruited from an MSM health clinic to provide semen and blood samples. Methods:HIV levels were assessed in paired semen and blood samples by PCR. Clinical and behavioral data were obtained from medical records and questionnaires. Herpes simplex virus 2 (HSV-2) serostatus, seminal HSV-2 DNA, and markers of genital inflammation were measured using standard laboratory methods. Results:Overall, HIV-1 was detected in 18 of 101 (18%) blood and 30 of 101 (30%) semen samples. Of 83 men with undetectable HIV in blood plasma, 25% had HIV in semen with copy numbers ranging from 80 to 2560. Multivariate analysis identified STI/urethritis (P = 0.003), tumor necrosis factor &agr; (P = 0.0003), and unprotected insertive anal sex with an HIV-infected partner (P = 0.007) as independent predictors of seminal HIV detection. Conclusion:STIs and genital inflammation can partially override the suppressive effect of HAART on seminal HIV shedding in sexually active HIV-infected MSM. Low seminal HIV titers could potentially pose a transmission risk in MSM, who are highly susceptible to HIV infection.

Beyond Assumptions of Negligible Risk: Sexually Transmitted Diseases and Women Who Have Sex With Women

OBJECTIVES This study evaluated the association of female-female sexual behavior with sexually transmitted diseases (STDs). METHODS Female participants (n = 286) were recruited from the Twin Cities Gay/Lesbian/Bisexual/Transgender Pride Festival. Logistic regression was used to examine the association between female-female sexual behavior and STDs. RESULTS Women in all partner history groups, including 13% of women with only female partners, reported a history of STD. Increased sexual exposures with women predicted an increase in the likelihood of STDs after known risk factors had been controlled. Neither number of female partners nor number of exposures was associated with obtaining regular STD testing. CONCLUSIONS The risk of STDs through female-female sexual exposure is not negligible. Nevertheless, patterns of STD testing do not reflect this risk.

Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: A meta-analysis

Objective: To evaluate treatment-mediated changes in HIV-1 RNA and CD3 count as prognostic markers and surrogate end points for disease progression (AIDS/death). Methods: Data from 13,045 subjects in all 16 randomized trials comparing nucleoside analogue reverse transcriptase inhibitors and having HIV-1 RNA measurements at 24 weeks were obtained. A total of 3146 subjects had HIV-1 RNA and CD3 count determinations at 24 weeks after starting treatment. Results: At Week 24, the percentage of subjects experiencing an HIV-1 RNA decrease of >1 log(10) copies/ml or a CD4 count increase of >33% was similar (22% vs 25%). Changes in both markers at Week 24 mere significant independent predictors of AIDS/death: across trials, the average reduction in hazard was 51% per 1 log(10) HIV-1 RNA copies/ml decrease (95% confidence interval: 41%, 59%) and 20% per 33% CD4 count increase (17%, 24%). In univariate analyses, the hazard ratio for AIDS/death in randomized treatment comparisons was significantly associated with differences between treatments in mean area under the curve of HIV-1 RNA changes to Weeks 8 and 24 (AUCMB) and mean CD3 change at Week 24, but, in multivariate analysis, only mean CD4 change was significant. Conclusions: Change in HIV-1 RNA, particularly using AUCMB, and in CD4 count should be measured to aid patient management and evaluation of treatment activity in clinical trials. However, short-term changes in these markers are imperfect as surrogate end points for long-term clinical outcome because two randomized treatment comparisons may show similar differences between treatments in marker changes but not similar differences in progression to AIDS/death.

History of childhood sexual abuse and unsafe anal intercourse in a 6-city study of HIV-positive men who have sex with men.

OBJECTIVES We assessed rates of childhood sexual abuse and its demographic and mental health correlates among HIV-positive men who reported unsafe anal intercourse with other men in the past year. METHODS We conducted a cross-sectional analysis of baseline data from 593 HIV-positive men who have sex with men enrolled in the Positive Connections intervention. RESULTS Childhood sexual abuse was reported by 47% of participants; 32% reported frequency as often or sometimes. Men reporting abuse were more likely to be Latino (odds ratio [OR] = 2.6; 95% confidence interval [CI] = 1.6, 4.2; P < .001) or African American (OR = 1.8; 95% CI = 1.2, 2.7; P = .005) than White. Among those who were abused, more frequent abuse was associated with more sexual contacts (for each, rate ratio [RR] = 1.3; P < .001) and unsafe anal intercourse (often, RR = 1.5; sometimes, RR = 2.0; P < .001) compared with men who were not abused. CONCLUSIONS History of childhood sexual abuse is highly prevalent among HIV-positive men who engage in risky sexual behavior with other men and appears to be more common among men of color. Our findings suggest that abuse is associated with a significantly increased risk of sexually transmitted infections.

Intimate partner violence perpetration, risky sexual behavior, and STI/HIV diagnosis among heterosexual African American men.

Evidence indicates that abusive male partners pose increased risk for sexually transmitted infection (STI)/HIV among females. However, research with males on this issue is limited. The objective of this study was to assess the associations between intimate partner violence (IPV) perpetration and recent STI/HIV diagnosis, unprotected sex, and sex trade involvement among heterosexual African American men. In this cross-sectional study, heterosexual African American males aged 18 to 65 years who reported two or more sex partners in the past year were recruited from urban health clinics to complete a computerized survey assessing sociodemographic characteristics, IPV perpetration history, risky sexual behaviors, and substance use. Multivariate logistic regression analyses assessed associations between IPV perpetration and STI/HIV risk. More than half of participants in this sample (61%) were unemployed; 28.2% had less than a high school education and 23.1% were homeless. One-fifth of the sample (21.2%) reported IPV perpetration in their current relationship. IPV perpetration was significantly associated with recent STI/HIV diagnosis, unprotected anal sex, and buying sex. IPV perpetration is pervasive among heterosexually at-risk African American men presenting for clinical care, and those perpetrating IPV are at heightened risk for STI/HIV.

Eicosanoid modulation of stress fibers in cultured bovine aortic endothelial cells.

Leukotrienes (LT) B4, LTD4, and thromboxanes (TX) are cytotoxic, and increase microvascular permeability. Because endothelial stress fibers are theorized to be part of the cytoskeletal mechanism by which microvessels maintain their barrier function, the effect of these eicosanoids on stress fibers in bovine aortic endothelial cells was tested. LTB4, LTD4, and TXB2 each decreased stress fiber numbers by 93%, 62%, and 66%, respectively, when compared to controls (P < 0.01). In contrast, endothelial cells treated with prostacyclin (PGI2) at 10−7 M, produced a significant increase (P >0.01) in stress fiber numbers, 211% to that of controls. Azaprostanoic acid (13-APA) and FPL55712, receptor antagonists to TX and slowreacting substance of anaphylaxis (SRS) receptors, respectively, the cyclooxygenase inhibitor ibuprofen, and the TX synthase inhibitors imidazole and ketoconazole were used to test for possible endothelial cell receptor mediation and de novo prostanoid synthesis associated with inflammatory eicosanoid-induced disassembly of stress fibers. Each pharmacologic agent inhibited the LTD4- and TXB2-induced decreases in stress fibers; LTB4-stimulated stress fiber decreases were inhibited only by pretreatment with TX synthase blockers. These data suggest that increased permeability associated with inflammatory eicosanoid metabolites may have as a common target stress fiber disassembly, and the mechanism may be receptor-mediated. That cyclooxygenase and TX synthase blockers inhibited the eicosanoid action suggests that endogenous TX synthesis may be a step in the mechanism. PGI2 enhancement of the microvascular barrier may be related to the effect of PGI2 on promoting stress fiber assembly. In summary, endothelial cell synthesized autocoids derived from arachidonic acid may help to regulate microvascular permeability by way of their action on stress fiber assembly/dissassembly, and unbalanced prostanoid secretion by way of LT stimulation may result in a loss of the microvascular barrier and increased permeability.