Sodsai Tovanabutra

Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2

The RV144 trial demonstrated 31% vaccine efficacy at preventing human immunodeficiency virus (HIV)-1 infection. Antibodies against the HIV-1 envelope variable loops 1 and 2 (Env V1 and V2) correlated inversely with infection risk. We proposed that vaccine-induced immune responses against V1/V2 would have a selective effect against, or sieve, HIV-1 breakthrough viruses. A total of 936 HIV-1 genome sequences from 44 vaccine and 66 placebo recipients were examined. We show that vaccine-induced immune responses were associated with two signatures in V2 at amino acid positions 169 and 181. Vaccine efficacy against viruses matching the vaccine at position 169 was 48% (confidence interval 18% to 66%; P = 0.0036), whereas vaccine efficacy against viruses mismatching the vaccine at position 181 was 78% (confidence interval 35% to 93%; P = 0.0028). Residue 169 is in a cationic glycosylated region recognized by broadly neutralizing and RV144-derived antibodies. The predicted distance between the two signature sites (21 ± 7 Å) and their match/mismatch dichotomy indicate that multiple factors may be involved in the protection observed in RV144. Genetic signatures of RV144 vaccination in V2 complement the finding of an association between high V1/V2-binding antibodies and reduced risk of HIV-1 acquisition, and provide evidence that vaccine-induced V2 responses plausibly had a role in the partial protection conferred by the RV144 regimen.

Magnitude and Breadth of the Neutralizing Antibody Response in the RV144 and Vax003 HIV-1 Vaccine Efficacy Trials

Background. A recombinant canarypox vector expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pro, and membrane-linked gp120 (vCP1521), combined with a bivalent gp120 protein boost (AIDSVAX B/E), provided modest protection against HIV-1 infection in a community-based population in Thailand (RV144 trial). No protection was observed in Thai injection drug users who received AIDSVAX B/E alone (Vax003 trial). We compared the neutralizing antibody response in these 2 trials. Methods. Neutralization was assessed with tier 1 and tier 2 strains of virus in TZM-bl and A3R5 cells. Results. Neutralization of several tier 1 viruses was detected in both RV144 and Vax003. Peak titers were higher in Vax003 and waned rapidly in both trials. The response in RV144 was targeted in part to V3 of gp120.vCP1521 priming plus 2 boosts with gp120 protein was superior to 2 gp120 protein inoculations alone, confirming a priming effect for vCP1521. Sporadic weak neutralization of tier 2 viruses was detected only in Vax003 and A3R5 cells. Conclusion. The results suggest either that weak neutralizing antibody responses can be partially protective against HIV-1 in low-risk heterosexual populations or that the modest efficacy seen in RV144 was mediated by other immune responses, either alone or in combination with neutralizing antibodies.

Protective Efficacy of a Global HIV-1 Mosaic Vaccine against Heterologous SHIV Challenges in Rhesus Monkeys

The global diversity of HIV-1 represents a critical challenge facing HIV-1 vaccine development. HIV-1 mosaic antigens are bioinformatically optimized immunogens designed for improved coverage of HIV-1 diversity. However, the protective efficacy of such global HIV-1 vaccine antigens has not previously been evaluated. Here, we demonstrate the capacity of bivalent HIV-1 mosaic antigens to protect rhesus monkeys against acquisition of infection following heterologous challenges with the difficult-to-neutralize simian-human immunodeficiency virus SHIV-SF162P3. Adenovirus/poxvirus and adenovirus/adenovirus vector-based vaccines expressing HIV-1 mosaic Env, Gag, and Pol afforded a significant reduction in the per-exposure acquisition risk following repetitive, intrarectal SHIV-SF162P3 challenges. Protection against acquisition of infection correlated with vaccine-elicited binding, neutralizing, and functional nonneutralizing antibodies, suggesting that the coordinated activity of multiple antibody functions may contribute to protection against difficult-to-neutralize viruses. These data demonstrate the protective efficacy of HIV-1 mosaic antigens and suggest a potential strategy for the development of a global HIV-1 vaccine. PAPERCLIP:

Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial

We analyzed HIV-1 genome sequences from 68 newly infected volunteers in the STEP HIV-1 vaccine trial. To determine whether the vaccine exerted selective T cell pressure on breakthrough viruses, we identified potential T cell epitopes in the founder sequences and compared them to epitopes in the vaccine. We found greater distances to the vaccine sequence for sequences from vaccine recipients than from placebo recipients. The most significant signature site distinguishing vaccine from placebo recipients was Gag amino acid 84, a site encompassed by several epitopes contained in the vaccine and restricted by human leukocyte antigen (HLA) alleles common in the study cohort. Moreover, the extended divergence was confined to the vaccine components of the virus (HIV-1 Gag, Pol and Nef) and not found in other HIV-1 proteins. These results represent what is to our knowledge the first evidence of selective pressure from vaccine-induced T cell responses on HIV-1 infection in humans.

Protection against sexually transmitted diseases by granting sex workers in Thailand the choice of using the male or female condom: results from a randomized controlled trial.

Background:The male condom is the most effective barrier method available for protection against sexually transmitted diseases (STDs), including HIV infection. There is an urgent need to develop and evaluate other prevention methods, such as the female condom. This study estimated the additional protection against STDs offered to sex workers by giving them the option of using the female condom when clients refused to use a male condom. Methods:Sex establishments in four cities in Thailand were randomized into two study groups: one in which sex workers were instructed to use male condoms consistently (male condom group); and one in which sex workers had the option of using the female condom if clients refused or were not able to use male condoms (male/female condom group). Randomization was done by sex establishments, and not by individuals, to minimize sharing of female condoms across study groups. The proportion of unprotected sexual acts (defined as sexual acts in which condoms were not used, tore, or slipped in or out) and incidence rate of STDs (gonorrhoea, chlamydial infection, trichomoniasis and genital ulcer disease) were measured over a 24-week period and compared between the two study groups. Findings:Results are available from 34 sex establishments (249 women) in the male/female condom group, and 37 sex establishments (255 women) in the male condom group. Condom use was very high in both groups (97.9 and 97.3 % of all sexual acts, respectively, P > 0.05). Male condom use was lower in the male/female condom group when compared with the male condom group (88.2 and 97.5%, respectively, P < 0.001). However, this reduction in male condom use was counterbalanced by the use of female condoms in 12.0% of all sexual acts in the male/female condom group, contributing to a 17% reduction in the proportion of unprotected sexual acts in this group when compared to the male condom group (5.9 versus 7.1%, respectively, P = 0.16). Female condom use was sustained over the entire study period. There was also a 24% reduction in the weighted geometric mean incidence rate of STDs in the sex establishments of the male/female condom group compared to the male condom group (2.81 versus 3.69 per 100 person-weeks, P = 0.18). Interpretation:The replacement of male condoms by female condoms in a proportion of sexual acts in the male/female condom group suggests that some sex workers and/or their clients preferred using the female condom. This switch in barrier method was accompanied by non-significant reductions in the proportion of unprotected sexual acts and in the incidence rate of STDs in the women of the male/female condom group. Special attention should be paid to a potential risk of slippage of the female condom in inexperienced users.

Drug use, increasing incarceration rates, and prison-associated HIV risks in Thailand.

Background: Incarceration is a known risk for HIV infection in Thai drug users. Through the 1990s, incarceration rates for drug-related offenses rose sharply, whereas HIV prevention and drug treatment in prisons remained limited. Methods: We assessed HIV and incarceration risks for injection drug users (IDU) and non-IDU in a large treatment center cohort in northern Thailand to investigate HIV and prison risks in this period. We used Thai Bureau of Corrections data to assess incarceration and prevention funds in prisons, 1992–2000. Results: Among 1,865 drug user in the treatment cohort, 503 (27.0%) had ever been jailed. Men (OR 3.3, 95% CI 2.1, 5.2), IDU (OR 6.3, 95% CI 5.1, 7.9), and men who have sex with men (MSM) (OR 3.4, 95% CI 1.8, 6.3) were more likely to have been jailed. Among male IDU who had ever been jailed (N = 272), 15.8% had used drugs in prison. In a multivariate model, incarceration and ever IDU remained independently associated with HIV infection; IDU, MSM behaviors, and harmful traditional practices remained independently associated with having been jailed. From 1992 to 2000, overall alleged narcotics offenses increased from 117,000 to 276,000/year. The number of persons incarcerated for narcotics offenses increased fivefold from 1992 to 1999, from 12,860 to 67,440. For FY 2000, narcotics treatment accounted for 0.06% of the Thai corrections budget, whereas HIV programs in prisons were 0.017%. Conclusions: Incarceration rates for narcotics offenses have increased sharply in Thailand, whereas prevention has lagged. Having been jailed is an important independent risk for HIV infection among Thai male drug users, especially IDU and MSM. HIV prevention and drug treatment are urgently needed in Thai prisons.

HIV prevalence and risks among injection and noninjection drug users in northern Thailand: need for comprehensive HIV prevention programs.

The authors sought to determine sociodemographic and sexual and drug use risk factors for HIV infection among drug users in northern Thailand adjacent to the Golden Triangle. The authors enrolled patients admitted for inpatient drug detoxification at one treatment center in northern Thailand and studied HIV risks and prevalence using an interviewer-administered questionnaire and serum collection with HIV pretest and posttest counseling. Between February 1, 1999 and January 31, 2000, 1865 patients admitted for opiate and methamphetamine dependence completed study procedures. Overall HIV prevalence was 10.3%: 30.0% among 513 injection drug users (IDUs) and 2.8% among non-IDUs (OR = 14.8, 95% CI: 10.2, 21.6). HIV seroprevalence was 2.4% among exclusive methamphetamine users (98% of whom are non-IDUs) and 3.4% among opium smokers. Injection drug use was the dominant risk factor in multivariate models. Although Thailand is widely recognized as having a successful national response to the heterosexual HIV epidemic, seroprevalence in IDUs remains high. Despite a sharp increase of non-IDUs admitted to the drug treatment center, HIV infection and risks remained high among IDUs in northern Thailand. HIV prevention campaigns need to focus on IDUs and to implement harm reduction strategies to reduce transmission to IDUs and further contain the HIV epidemic in Thailand.

Prospective Study of Acute HIV-1 Infection in Adults in East Africa and Thailand

BACKGROUND Acute human immunodeficiency virus type 1 (HIV-1) infection is a major contributor to transmission of HIV-1. An understanding of acute HIV-1 infection may be important in the development of treatment strategies to eradicate HIV-1 or achieve a functional cure. METHODS We performed twice-weekly qualitative plasma HIV-1 RNA nucleic acid testing in 2276 volunteers who were at high risk for HIV-1 infection. For participants in whom acute HIV-1 infection was detected, clinical observations, quantitative measurements of plasma HIV-1 RNA levels (to assess viremia) and HIV antibodies, and results of immunophenotyping of lymphocytes were obtained twice weekly. RESULTS Fifty of 112 volunteers with acute HIV-1 infection had two or more blood samples collected before HIV-1 antibodies were detected. The median peak viremia (6.7 log10 copies per milliliter) occurred 13 days after the first sample showed reactivity on nucleic acid testing. Reactivity on an enzyme immunoassay occurred at a median of 14 days. The nadir of viremia (4.3 log10 copies per milliliter) occurred at a median of 31 days and was nearly equivalent to the viral-load set point, the steady-state viremia that persists durably after resolution of acute viremia (median plasma HIV-1 RNA level, 4.4 log10 copies per milliliter). The peak viremia and downslope were correlated with the viral-load set point. Clinical manifestations of acute HIV-1 infection were most common just before and at the time of peak viremia. A median of one symptom of acute HIV-1 infection was recorded at a median of two study visits, and a median of one sign of acute HIV-1 infection was recorded at a median of three visits. CONCLUSIONS The viral-load set point occurred at a median of 31 days after the first detection of plasma viremia and correlated with peak viremia. Few symptoms and signs were observed during acute HIV-1 infection, and they were most common before peak viremia. (Funded by the Department of Defense and the National Institute of Allergy and Infectious Diseases.).

Risk factors for HIV-1 transmission from HIV-seropositive male blood donors to their regular female partners in northern Thailand.

Objective:To describe risks for HIV transmission from male blood donors to their regular female sex partners in Chiang Mai, Thailand. Design:Cross-sectional study. Methods:From March 1992 through September 1995, 405 HIV-seropositive male blood donors (index cases) and their regular female partners were enrolled in the study. Women with risk factors for HIV infection other than sexual contact with the index male were excluded. Couples were interviewed and examined; specimens were collected for laboratory analysis. Results:Overall, 46% of the 405 women enrolled were HIV-positive. Ninety-eight per cent of male index cases had a history of sex with a female prostitute; 1.5% reported always using condoms with their regular partner. History of sexually transmitted disease (STD) and swollen inguinal lymph nodes in the female partner were associated with an increased risk of HIV infection in the female. History in the female of genital herpes [odds ratio (OR), 3.46; 95% confidence interval (CI), 1.50–8.78], gonorrhea or chlamydia infection (OR, 2.71; 95% CI, 1.39–5.53), and stable relationship of longer than 24 months (OR, 2.28; 95% CI, 1.02–5.09) were associated with an increased risk of HIV infection in the female. Consistent condom use in the past 2 years (OR, 0.10; 95% CI, 0.01–0.79) was associated with a decreased risk of HIV infection in the female. Conclusions:Married women in northern Thailand who appear otherwise to be at low risk for HIV infection may be exposed to this virus by their husbands. High rates of sex with commercial sex workers among men and low use of condoms within stable relationships may be important factors promoting the transmission of HIV in married couples. Programs to increase the regular use of condoms among married couples could be an important public health intervention to prevent transmission of HIV and other types of STD in northern Thailand.

In-Depth, Longitudinal Analysis of Viral Quasispecies from an Individual Triply Infected with Late-Stage Human Immunodeficiency Virus Type 1, Using a Multiple PCR Primer Approach

ABSTRACT Coinfections with more than one human immunodeficiency virus type 1 (HIV-1) subtype appear to be the source of new recombinant strains and may be commonplace in high-risk cohorts exposed to multiple subtypes. Many potential dual infections have been identified during the HIV Superinfection Study in Mbeya, Tanzania, where 600 female bar workers who are highly exposed to subtypes A, C, and D have been evaluated every 3 months for over 3 years by use of the MHAacd HIV-1 genotyping assay. Here we describe an in-depth, longitudinal analysis of the viral quasispecies in a woman who was triply infected with HIV-1 and who developed AIDS and passed away 15 months after enrollment. The MHA results obtained at 0, 3, 6, 9, and 12 months revealed dual-probe reactivities and shifts in subtype over time, indicating a potential dual infection and prompting further investigation. The multiple infection was confirmed by PCR amplification of three genome regions by a multiple primer approach, followed by molecular cloning and sequencing. A highly complex viral quasispecies was found, including several recombinant forms, with vpu/gp120 being the most diverse region. A significant fluctuation in molecular forms over time was observed, showing that the serial sample format is highly desirable, if not essential, for the identification of multiple infections. In a separate experiment, we confirmed that the detection of coinfections is more efficient with the use of multiple amplification primers to overcome the primer bias that results from the enormous diversity in the HIV-1 genome.