Melissa R. Krone

Relationship between T Cell Activation and CD4+ T Cell Count in HIV-Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy

BACKGROUND Although untreated human immunodeficiency virus (HIV)-infected patients maintaining undetectable plasma HIV RNA levels (elite controllers) have high HIV-specific immune responses, it is unclear whether they experience abnormal levels of T cell activation, potentially contributing to immunodeficiency. METHODS We compared percentages of activated (CD38(+)HLA-DR(+)) T cells between 30 elite controllers, 47 HIV-uninfected individuals, 187 HIV-infected individuals with undetectable viremia receiving antiretroviral therapy (antiretroviral therapy suppressed), and 66 untreated HIV-infected individuals with detectable viremia. Because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection, we also measured plasma lipopolysaccharide (LPS) levels. RESULTS Although the median CD4(+) cell count in controllers was 727 cells/mm(3), 3 (10%) had CD4(+) cell counts <350 cells/mm(3) and 2 (7%) had acquired immunodeficiency syndrome. Controllers had higher CD4(+) and CD8(+) cell activation levels (P < .001 for both) than HIV-negative subjects and higher CD8(+) cell activation levels than the antiretroviral therapy suppressed (P = .048). In controllers, higher CD4(+) and CD8(+) T cell activation was associated with lower CD4(+) cell counts (P = .009 and P = .047). Controllers had higher LPS levels than HIV-negative subjects (P < .001), and in controllers higher LPS level was associated with higher CD8(+) T cell activation (P = .039). CONCLUSION HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia.

Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy

Objective: To determine the extent to which HIV-infected patients, including those with advanced immunodeficiency, can reverse peripheral CD4 T-cell depletion while maintaining long-term viral suppression on highly active antiretroviral therapy. Design: Cohort study. Participants: Four-hundred and twenty-three HIV-infected patients who initiated HAART prior to 1998 and achieved a viral load ⩽ 1000 copies/ml by 48 weeks were evaluated for up to 4 years or until plasma HIV RNA levels increased to > 1000 copies/ml. Main outcome measure: CD4 count changes. Results: Among patients who maintained plasma HIV RNA levels ⩽ 1000 copies/ml, CD4 counts continued to increase through year 4 of HAART. In the last year examined, from year 3 to 4 of HAART, mean CD4 count gains were +89 × 106, +86 × 106, +95 × 106, and +88 × 106/l in patients with pre-therapy CD4 counts of < 50 × 106, 50 × 106–199 × 106, 200 × 106–349 × 106, and ⩾ 350 × 106/l, respectively (all gains were significantly greater than zero; P < 0.05). Among those with a pre-therapy CD4 count of < 50 × 106/l, 88% achieved a CD4 cell count of ⩾ 200 × 106/l and 59% achieved a count of ⩾ 350 × 106/l by year 4. Factors associated with increased CD4 cell count gains from month 3 to year 4 included lower pre-therapy CD4 cell count, younger age, female sex, and infrequent low-level viremia (versus sustained undetectable viremia). Conclusions: Most patients who achieve and maintain viral suppression on HAART continue to experience CD4 T-cell gains through 4 years of therapy. The immune systems capacity for CD4 T lymphocyte restoration is not limited by low pre-therapy CD4 counts.

Protection against Human Immunodeficiency Virus Type 1 Infection in Persons with Repeated Exposure: Evidence for T Cell Immunity in the Absence of Inherited CCR5 Coreceptor Defects

It has been hypothesized that protection against human immunodeficiency virus (HIV)-1 infection may result from either acquired host immunity, inheritance of a dysfunctional CCR5 HIV-1 coreceptor, or a low or attenuated virus inoculum. Thirty-seven HIV-1-uninfected persons engaging in repeated high-risk sexual activity with an HIV-1-infected partner were prospectively studied to determine the contribution of these factors in protecting against HIV-1 transmission. More than one-third (13/36) demonstrated HIV-1-specific cytotoxicity, and this activity significantly correlated with the wild type CCR5 genotype (P=.03). Only 1 subject (3%) demonstrated the homozygous CCR5 32-bp deletion (Delta32/Delta32). Median plasma HIV-1 RNA levels from 18 HIV-1-infected sex partners were not statistically different from those of matched infected control patients. These results indicate that inheritance of the Delta32 CCR5 mutation does not account for the majority of persistently HIV-1-resistant cases, and the presence of cellular immunity in these persons suggests either undetected infection or protective immunity.

Use of postexposure prophylaxis against HIV infection following sexual exposure does not lead to increases in high-risk behavior

Background: The effectiveness of postexposure prophylaxis (PEP) following occupational exposure to HIV has prompted advocacy for PEP following sexual or drug-use exposures. Objective: To evaluate the concern that the availability of PEP for sexual or drug-use exposures might result in behavioral disinhibition. Design: Non-randomized trial of 397 adults with high-risk sexual or drug-use exposures within the prior 72 h. Interventions: Antiretroviral medication for 4 weeks and five counseling sessions. Main outcome measurements: Participants were followed for 12 months for repeat request for PEP and for changes compared with pre-enrollment in overall high-risk behavior and the acquisition of sexually transmitted diseases (STD) and HIV. Results: After 12 months following receipt of PEP, the majority of participants (83%) did not request a repeat course of PEP. At 12 months after exposure, 73% of participants reported a decrease compared with baseline in the number of times they had performed high-risk sexual acts; 13% reported no change, and 14% had an increase. Most participants (85%) had no change in the incidence of STD; 8.5% had a decrease and 6.8% an increase. Three homosexual men seroconverted for HIV (none associated with the presenting exposure) for a rate of 1.2/100 person-year, equivalent to rates in San Francisco among all homosexual men. Conclusions: After receipt of PEP consisting of antiretroviral medication and behavioral counseling following a potential sexual exposure to HIV, most individuals do not increase high-risk behavior. Coupled with prior safety and feasibility data, this lack of behavioral disinhibition suggests that use of PEP should be routinely considered following high-risk sexual exposures.

Seroconversion following nonoccupational postexposure prophylaxis against HIV

BACKGROUND The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP. METHODS HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation. RESULTS Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverters virus. CONCLUSIONS As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.

HIV+ elite controllers have low HIV-specific T-cell activation yet maintain strong, polyfunctional T-cell responses.

Objective:HIV+ elite controllers are a unique group of rare individuals who maintain undetectable viral loads in the absence of antiretroviral therapy. We studied immune responses in these individuals to inform vaccine development, with the goal of identifying the immune correlates of protection from HIV. Methods:We compared markers of cellular activation, HIV-specific immune responses and regulatory T (Treg) cell frequencies in four groups of individuals: HIV-negative healthy controls, elite controllers (HIV RNA level <75 copies/ml), individuals on HAART and individuals with HIV RNA level more than 10 000 copies/ml (noncontrollers). Results:Elite controllers possessed significantly lower levels of activated HIV-specific CD8+ T cells and of recently divided HIV-specific CD4+ T cells than noncontrollers, whereas these differences were not seen in the respective cytomegalovirus-specific T-cell populations. Elite controllers also mounted a stronger and broader cytokine and chemokine response following HIV-specific stimulation than individuals on HAART and noncontrollers. Finally, we found that HAART-suppressed individuals had elevated Treg cell frequencies, whereas elite controllers and noncontrollers maintained normal percentages of Treg cells. Conclusion:Elite controllers maintain high levels of HIV-specific immune responses with low levels of HIV-specific T-cell activation and do not have elevated Treg cell levels. Based on these data an ideal HIV vaccine would induce strong HIV-specific immune responses whereas minimizing HIV-specific T-cell activation.

Patients attending STD clinics in an evolving health care environment. Demographics, insurance coverage, preferences for STD services, and STD morbidity.

Objectives: To characterize client demographics, sexually transmitted diseases (STD) morbidity, insurance status, reasons for attending public STD clinics, and future preferences for source of STD services. Design: Cross‐sectional study of 2,490 clients attending five urban STD clinics for new problems with interviewer‐administered 23‐item questionnaire and chart review to obtain clinical and laboratory STD diagnoses. Results: Participants were young (51% <25 years of age), minority (64% nonwhite), poor (43% ≤

Incidence of HIV and sexually transmitted diseases (STD) in a cohort of HIV-negative men who have sex with men (MSM).

10,000/year), and largely uninsured (59% uninsured, 27% private insurance, and 14% Medicaid). Half had previously visited the STD clinic, and 81% had used other providers for non‐STD services in the prior 3 years. STD symptoms were cited as the reason for the visit by 63%. The most common factors associated with seeking care at these STD clinics were walk‐in services, costs, and confidentiality concerns. STD morbidity was high; 66% of clients were diagnosed with one or more STD. Most (68%) clients preferred to be treated at the STD clinic in the future if they could go anywhere for STD services. Conclusions: STD clinics see young, minority, poor, and uninsured clients with high STD rates. Even with unlimited future choice, two thirds of the clients surveyed would still prefer to be treated at STD clinics. This study indicates the continuing need for publicly funded, categorical STD clinics in urban areas with high STD morbidity and the importance of easily accessible, confidential, expert STD services from the private sector and managed care organizations.

Sexual behaviors and risk factors for HIV infection among men who have sex with men in the Dominican Republic.

Objective:To determine the prevalence of sexually transmited diseases (STD) and incidence of and risk factors for STD, including HIV-1, among a cohort of HIV-negative men who have sex with men (MSM). Setting:Seattle, Washington, United States. Participants:Prospective cohort of 578 HIV-negative MSM in which risk factors for acquiring a STD over 12 months follow-up were evaluated using a cumulative incidence analysis. Main outcome measures:Baseline tests obtained were: herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) Western blots, hepatitis B, and syphilis serologies; anorectal and pharyngeal Neisseria gonorrhoeae (GC) cultures; first-catch urine for leukocyte esterase (LE) and Chlamydia trachomatis (CT) ligase chain reaction (LCR). Men with a positive urine LE had urethral GC cultures obtained. The following outcomes were measured over 12 months follow-up: incident symptomatic bacterial STD (urethritis, proctitis, epididymitis), HSV-1 and HSV-2 seroconversion, and HIV-1 seroconversion. The 31 incident cases of STD (men with bacterial STD) were compared with those 489 men without symptomatic bacterial STD or seroconversion to HSV-1, HSV-2 or HIV-1 infection. Results:Bacterial STD were found in nine participants at enrollment; there were two cases of nonchlamydial urethritis, two cases of nonchlamydial epididymitis, and five cases of asymptomatic GC infection. At enrollment, HSV-2 antibodies were detected in 149 (26.0%) of 572 men and prior hepatitis B infection in 145 (34.8%) of 417 unvaccinated men. During the 1-year of follow-up, 31 men (5.7/100 person-years) had 34 episodes of a symptomatic bacterial STD syndrome (urethritis, epididymitis or proctitis). Urethritis was the most common STD syndrome, detected in 29 men, of whom 10 had GC and 19 had nongonococcal urethritis. In the 1-year of follow-up, five participants seroconverted to HIV-1 (1.3/100 person-years), four to HSV-2 (1.0/100 person-years), and seven to HSV-1 (4.3/100 person-years). Unprotected insertive anal sex [odds ratio (OR) 2.6; 95% confidence interval (CI) 1.2–5.6]; and nitrite inhalant (‘poppers’) use (OR, 2.3; 95% Cl, 1.0–5.0) were independently associated with incident STD. Conclusions:STD and HIV infection continue to be acquired even in a city with an overall low bacterial STD prevalence and among educated MSM receiving regular HIV screening and risk-reduction. Urethritis was the most common STD detected, and public health messages aimed at MSM need to emphasize safe insertive as well as receptive sexual practices.

Clients of female sex workers in Lima, Peru: A bridge population for sexually transmitted disease/HIV transmission?

Objective:To describe self-reported types of sexual identity of men who have sex with men (MSM) in the Dominican Republic, assess sociodemographics and behavioral characteristics, and measure the prevalence of HIV-1 and syphilis. Design:Cross-sectional study of MSM recruited from a variety of community settings. Methods:A total of 354 men agreed to participate after giving verbal informed consent. Information was obtained using a standardized questionnaire assessing demographics and AIDS-relevant information. Blood was obtained for HIV and syphilis testing. Results:Five main sexual identity groups emerged: cross dressers, homosexuals, gigolos, bisexuals and heterosexuals. Receptive anal and oral intercourse were commonly reported by men self-identifying as cross dressers or homosexuals, whereas nearly all of the remaining three groups practiced only insertive intercourse. Sexual contact with women was also commonly reported; overall, consistent condom use was infrequent. HIV antibodies were detected in 11.0% and serologic evidence of syphilis was found in 7.3%. Factors independently associated with HIV infection included serologic evidence of syphilis, having visited at least one of four local brothels in 1975–1985, and having had receptive anal intercourse with four or more partners in the last 12 months. Conclusions:Syphilis, sexual practices and social context of sex (commercial sex), rather than sexual identity per se, were associated with HIV infection. The complex social networks of MSM in this setting, the tendency to practice either insertive or receptive sex, but not both, infrequent condom use, high rates of syphilis and the frequency of sex with women need to be taken into account for targeted HIV prevention programs to be successful.