Thomas C.Quinn, M.D., M.Sc.

Senior Investigator

Description of Research Program

Internationally, there are 36 million HIV-infected individuals and 24 million people have already died from AIDS. A major focus within our laboratory has been to define the unique epidemiologic, clinical, virologic, and immunologic features of HIV-1 and HIV-2 infections in developing countries and in the U.S.

 In a multicenter study on perinatal transmission in the U.S., we determined that elevated RNA viral levels at birth were suggestive of in utero infection and that a high plasma RNA viral load in the first two months of life (>300,000 copies per ml) was strongly associated with rapid progression to AIDS or death. None of the infants with <70,000 copies/ml progressed to AIDS, suggesting that antiretroviral therapy in infants with high viral loads should result in improved survival and delayed progression.

We subsequently studied maternal HIV RNA levels, which were found to be highly predictive of risk of perinatal transmission. For example, transmission rates increased from 0% to 40% for mothers with RNA levels <1,000 to over 100,000 copies/ml, respectively. The highest risk of transmission occurred in women with RNA levels >100,000 copies/ml who were not on zidovudine (63% transmission). Maternal viral load was the strongest of four independent predictors of transmission risk that included zidovudine use, duration of ruptured membranes greater than 4 hours, and birth weight <2500g. Additional studies on HIV viral load demonstrated that at the time of an acute opportunistic infection, HIV RNA may increase three to fivefold, which subsequently declines to the baseline viral RNA level 3 months following successful treatment. The changes in viral RNA correlated best with changes in cytokines associated with immune activation.

In Pune, India, we have screened 8,134 patients attending STD clinics, of whom 23% were HIV positive. In a prospective study, the incidence rate of HIV infection was 16.2% among female sex workers, 7.4% among men and 6.6% among married spouses of these men. The high frequency of multiple STDs and HIV infection coupled with low rates of condom use and low AIDS awareness highlights the rapid spread of HIV into both high and lower risk populations in India. In this study of 3,874 HIV antibody-negative persons, 58 were p24 antigen positive and subsequently seroconverted. Unprotected sexual contact with a commercial sex worker in the presence of an active genital ulcer at the time of screening was significantly associated with seroconversion. Signs and symptoms independently associated with p24 antigenemia included fever, arthralgias, and night sweats. Thus, screening for p24 antigen in HIV antibody-negative persons was found to be a reliable and effective method for determining recent risk behavior and identifying clinical signs of acute primary HIV infection.

In a community-based STD mass treatment campaign of 14,000 individuals in Uganda, there was a 60% in reduction in the prevalence and incidence of bacterial STDs, but the incidence of HIV infection was unaffected. Additional future studies will address the effect of mass treatment of STDs during pregnancy on perinatal outcomes.

In men, plasma HIV RNA levels after acute HIV seroconversion are an independent predictor of progression to AIDS. We identified a gender difference in viral load between men and women in a cross-sectional study and the predictive value of an RNA level for progression to AIDS appeared to be different in men and women. We therefore conducted a nested case-controlled study of RNA levels in both male and female injecting drug users in order to provide a longitudinal perspective on viral levels in men and women who progress to AIDS compared to male and female non-progressors. Initial median viral load levels after seroconversion were significantly lower in women compared to men (15,000 copies/ml) compared to 150,000 copies/ml). Similarly, median plasma viral load was significantly lower among female compared to male non-progressors (12,000 vs. 61,000), and the initial viral load in women at seroconversion did not predict progression to AIDS, although the viral load was highly predictive for AIDS in men.

Among both men and women there was a steady increase in viral load levels among rapid progressors compared to controls and the difference between genders appeared to dissipate after four years of infection. This study demonstrated that plasma HIV RNA levels were significantly lower in women than men at the time of serconversion although this difference subsequently diminished after four years of infection. Plasma viral load at seroconversion in women is not as predictive of progression to AIDS as it is in men, and consequently viral load differences in women compared to men need to be taken into account when considering when to initiate antiretroviral therapy.

Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen in the United States with an incidence of 4.5 million cases annually. The objectives of this project are to assess the frequency of C. trachomatis infections in selected populations, to develop and evaluate sensitive nucleic amplification assays for diagnosis, and to study the immunopathogenesis of C. trachomatis and C. pneumoniae infections.

Using molecular amplification assays, we screened over 2,000 male and 20,000 female patients in Baltimore. The overall prevalence of chlamydia ranged from 7% in family planning clinics to over 20% in adolescents. In a prospective study of 3,202 sexually active adolescents aged 12 to 19 years, chlamydia infection was found in 24% of first visits and 14% of repeat visits; 29% of adolescent females have at least one positive test in a one-year period. Females aged 14 years had the highest age-specific chlamydia prevalence rate of 27.5%. The chlamydia incident rate was 28 cases per 1,000 person-months with a median time of 6 months to re-infection. With such high rates of infection, we recommend screening all sexually active adolescent females for chlamydia infection at least twice yearly.

We also screened urine by ligase chain reaction (LCR) for C. trachomatis in 13,204 new female U.S. Army recruits from 50 states and four territories. The overall prevalence was 9% with a peak of 12% in 17-year-old females. Recent vaginal sex, young age (<25 years), being African American, having more than one sex partner, and inconsistent condom use were independently associated with chlamydia infection. In this national survey, we documented that the prevalence of chlamydia infection was very high in female military recruits and that all recruits should be screened and treated for chlamydia in order to reduce infection, transmission, and sequelae.

Internationally, in a community-based trial of mass STD treatment in the Rakai district of Uganda, we documented relatively high rates of chlamydia and gonorrhea in 15-24 year-olds (5%). Ten months after mass antibiotic treatment, there was a 50% reduction in both chlamydia and gonococcal infection. This study also demonstrated that the vast majority of STD infections are asymptomatic (80%), and that mass antibiotic treatment is effective in lowering infection rates. Future studies will address the effectiveness of mass treatment in limiting HIV transmission.

We recently demonstrated a direct correlation between C. pneumoniae and atherosclerotic heart disease by the recent isolation of C. pneumoniae in an explanted heart with severe coronary atherosclerosis. C. pneumoniae has also been demonstrated in nearly 50% of coronary and carotid atheromas by immunocytochemistry and/or PCR. In vitro studies have demonstrated that C. pneumoniae can infect and proliferate in coronary artery endothelial cells and aortic artery smooth muscle cells. In preliminary animal studies, C. pneumoniae-inoculated mice appeared to have an increased rate of atheroma formation in the carotid artery and aortic artery compared to control animals, suggesting an etiologic or co-factor role in the development of atherogenesis. Future studies will continue to examine the etiologic role and immunopathogenesis of C. pneumoniae in the development of atherosclerosis.

Research Group Members

John G. Bartlett, Robert C. Bollinger, Richard E. Chaisson, Charlotte A. Gaydos, Anne M. Rompalo, Sheila West, Jonathan M. Zenilman

Awards

AOA Epidemiology Research Award; Charles C. Shepard Science Award; James H. Nakano Citation for Outstanding Scientific Publication; USPHS Outstanding Service Award; USPHS Meritorious Service Award; USPHS Distinguished Service Award

Memberships

• American Association for the Advancement of Science
• Association of American Physicians
• American College of Physicians
• American Society for Microbiology
• American Society for Tropical Medicine and Hygiene
• American Federation for Clinical Research
• American Society for Clinical Investigation
• American Sexually Transmitted Diseases Association
• Infectious Disease Society of America
• IUSTI

Editorial Boards

• AIDS Research and Human Retroviruses
• AIDS
• Infectious Diseases in Clinical Practice
• Journal of AIDS
• The Journal of Infectious Diseases
• Sexually Transmitted Diseases

Advisory/Review Boards

• U.S.-Japan Cooperative Medical Science Program
• Panel Member, Committee on Population, National Academy of Sciences; WHO Program on Human Reproduction
• USPHS/IDSA Committee on Guidelines for the Prevention of Opportunistic Infections
• Scientific Program Committee for IDSA
• Scientific Review Committee, World AIDS Foundation
• Scientific Advisory Committee, International AIDS Vaccine Initiative

Selected Publications

(View list in PubMed.)

Garcia PM, Kalish LA, Pitt J, Minkoff H, Quinn TC, Burchett SK, Jackson B, Hanson C, Moey J, Diaz C, Smeriglio V, Lew JF. The role of maternal HIV-1 RNA in perinatal transmission: biological and clinical implications. The New England Journal of Medicine 1999;341:394-402.

Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li CJ, Wabwire-Mangen F, Meehan MP, Lutalo T, Rakai Project Study Group, Gray RH. Viral load and the risk of heterosexual transmission of human immunodeficiency virus type 1 among sexual partners. The New England Journal of Medicine 2000;342:921-929.

Quinn TC, Brookmeyer R, Kline R, Shepherd M, Paranjape R, Mehendale S, Gadkari DA, Bollinger RC. Feasibility, accuracy and cost savings of pooling sera for HIV-1 viral RNA for the diagnosis of acute primary HIV-1 infection and estimation of HIV-1 incidence. AIDS 2000;14:2751-2757.

Gray RH, Kiwanuka N, Wawer MJ, Sewankambo NK, Serwadda D, Wabwire Mangen F, Lutalo T, Nalugoda F, Kelly R, Meehan M, Chen MZ, Li C, Quinn TC and the Rakai Project Team. Male circumcision and HIV acquisition and transmission: cohort studies in Rakai, Uganda. AIDS 2000;14:2371-2381.

Howell MR, McKee K Jr., Quinn TC, Gaydos JC, Gaydos CA. Point-of-entry screening for C. trachomatis in female Army recruits: who derives the benefit? American Journal of Preventive Medicine 2000;19:160-166.

Sterling TR, Vlahov D, Astemborski J, Hoover DR, Margolick JB, Quinn TC. The relationship between initial HIV-1 RNA level after seroconversion and progression to AIDS in women and men: implications for initiation of antiretroviral therapy. New England Journal of Medicine 2001:344:720-5.

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