Background

Follow up of Human Immunodeficiency Virus (HIV)-exposed infants is an important component of Prevention of Mother-to-Child Transmission (PMTCT) programmes in order to ascertain infant outcomes post delivery. We determined HIV transmission, mortality and loss to follow-up (LTFU) of HIV-exposed infants attending a postnatal clinic in an urban hospital in Durban, South Africa.

Methods

We conducted a retrospective cohort study of infants born to women in the PMTCT programme at McCord Hospital, where mothers paid a fee for service. Data were abstracted from patient records for live-born infants delivered between 1 May 2008 and 31 May 2009. The infants’ LTFU status and age was based on the date of the last visit. HIV transmission was calculated as a proportion of infants followed and tested at six weeks. Mortality rates were analyzed using Kaplan-Meier (K-M), with censoring on 15 January 2010, LTFU or death.

Results

Of 260 infants, 155 (59.6%) remained in care at McCord beyond 28 weeks: one died at < 28 days, three died between one to six months; 34 were LTFU within seven days, 60 were LTFU by six months. K-M mortality rate: 1.7% at six months (95% confidence interval (CI): 0.6% to 4.3%). Of 220 (83%) infants tested for HIV at six weeks, six (2.7%, 95% CI: 1.1% to 5.8%) were HIV-infected. In Cox regression analysis, late antenatal attendance (≥ 28 weeks gestation) relative to attending in the first trimester was a predictor for infant LTFU (adjusted hazards ratio = 2.3; 95% CI: 1.0 to 5.1; p = 0.044).

Conclusion

This urban PMTCT programme achieved low transmission rates at six weeks, but LTFU in the first six months limited our ability to examine HIV transmission up to 18 months and determinants of mortality. The LTFU of infants born to women who attended antenatal care at 28 weeks gestation or later emphasizes the need to identify late antenatal attendees for follow up care to educate and support them regarding the importance of follow up care for themselves and their infants.

The response of prostate cells to androgens reflects a combination of androgen receptor (AR) transactivation and transrepression, but how these two processes differ mechanistically and influence prostate cancer risk and disease outcome remain elusive. Given recent interest in targeting AR transrepressive processes, a better understanding of AR/corepressor interaction and responses is warranted. Here, we used transactivation and interaction assays with wild-type and mutant ARs, and deletion AR fragments, to dissect the relationship between AR and the corepressor, silencing mediator for retinoic acid and thyroid hormone receptors (SMRT). We additionally tested how these processes are influenced by AR agonist and antagonist ligands, as well as by variation in the polyglutamine tract in the AR amino terminal domain (NTD), which is encoded by a polymorphic CAG repeat in the gene. SMRT was recruited to the AR ligand binding domain by agonist ligand, and as determined by the effect of strategic mutations in activation function 2 (AF-2), requires a precise conformation of that domain. A distinct region of SMRT also mediated interaction with the AR-NTD via the transactivation unit 5 (TAU5; residues 315–538) region. The degree to which SMRT was able to repress AR increased from 17% to 56% as the AR polyglutamine repeat length was increased from 9 to 42 residues, but critically this effect could be abolished by increasing the SMRT:AR molar ratio. These data suggest that the the extent to which the CAG encoded polyglutamine repeat influences AR activity represents a balance between corepressor and coactivator occupancy of the same ligand-dependent and independent AR interaction surfaces. Changes in the homeostatic relationship of AR to these molecules, including SMRT, may explain the variable penetrance of the CAG repeat and the loss of AR signalling flexibility in prostate cancer progression.

(See the editorial commentary by Mbulaiteye an Goedert, on pages 575–7.)

Background. Human herpesvirus 8 (HHV-8) infection is endemic in sub-Saharan Africa. We examined sociodemographic, behavioral, and biological factors associated with HHV-8 infection in children and adults to determine HHV-8 seroprevalence and potential routes of transmission.

Methods. Participants were 1383 children and 1477 adults from a population-based sample in a rural community in Uganda. Serum samples were tested for HHV-8 antibodies with use of an enzyme immunoassay against K8.1.

Results. HHV-8 seroprevalence increased from 16% among children aged 1.5–2 years to 32% among children aged 10–13 years (P <.001) and from 37% among participants aged 14–19 years to 49% among adults aged ≥50 years (P <.05). HHV-8 seropositivity in children was independently associated with residing with a seropositive parent (P < .001) and residing with ≥1 other seropositive child aged <14 years (P < .001). History of sharing food and/or sauce plates was marginally associated with HHV-8 infection in children (P = .05). Among 1404 participants aged ≥15 years , there was no association between correlates of sexual behavior (eg, number of lifetime sex partners and HIV infection) and HHV-8 seropositivity (P > .10).

Conclusions. Our data suggest that HHV-8 is acquired primarily through horizontal transmission in childhood from intrafamilial contacts and that transmission continues into adulthood potentially through nonsexual routes.

Equatorial Africa has among the highest incidences of Kaposi’s sarcoma (KS) in the world, thus earning the name “KS Belt.” This was the case even prior to the HIV . To date, there is no clear evidence that HHV-8 seroprevalence is higher in this region, but interpretation of the available literature is tempered by differences in serologic assays used across studies. We examined representatively sampled ambulatory adults in Uganda, which is in the “KS Belt”, and in Zimbabwe and South Africa which are outside the Belt, for HHV-8 antibodies. All serologic assays were uniformly performed in the same reference laboratory by the same personnel. In the base-case serologic algorithm, seropositivity was defined by reactivity in an immunofluorescence assay or in two enzyme immunoassays. A total of 2375 participants were examined. In Uganda, HHV-8 seroprevalence was high early in adulthood (35.5% by age 21) without significant change thereafter. In contrast, HHV-8 seroprevalence early in adulthood was lower in Zimbabwe and South Africa (13.7% and 10.8%, respectively), but increased with age. After age adjustment, Ugandans had 3.24-fold greater odds of being HHV-8-infected than South Africans (p<0.001) and 2.22-fold greater odds than Zimbabweans (p<0.001). Inferences were unchanged using all other serologic algorithms evaluated. In conclusion, HHV-8 infection is substantially more common in Uganda than in Zimbabwe and South Africa. These findings help explain the high KS incidence in the “KS Belt” and underscore the importance of a uniform approach to HHV-8 antibody testing.

DNA methylation plays an important role in carcinogenesis and the reversibility of this epigenetic modification makes it a potential therapeutic target. To date, DNA methyltransferase inhibitors (DNMTi) have not demonstrated clinical efficacy in prostate cancer, with one of the major obstacles being the inability to monitor drug activity during the trial. Given the high frequency and specificity of GSTP1 DNA methylation in prostate cancer, we investigated whether GSTP1 is a useful marker of DNMTi treatment efficacy. LNCaP prostate cancer cells were treated with 5-aza-2′-deoxycytidine (5-aza-CdR) either with a single high dose (5–20 µM), every alternate day (0.1–10 µM) or daily (0.005–2.5 µM). A daily treatment regimen with 5-aza-CdR was optimal, with significant suppression of cell proliferation achieved with doses of 0.05 µM or greater (p<0.0001) and induction of cell death from 0.5 µM (p<0.0001). In contrast, treatment with a single high dose of 20 µM 5-aza-CdR inhibited cell proliferation but was not able to induce cell death. Demethylation of GSTP1 was observed with doses of 5-aza-CdR that induced significant suppression of cell proliferation (≥0.05 µM). Re-expression of the GSTP1 protein was observed only at doses of 5-aza-CdR (≥0.5 µM) associated with induction of cell death. Treatment of LNCaP cells with a more stable DNMTi, Zebularine required at least a 100-fold higher dose (≥50 µM) to inhibit proliferation and was less potent in inducing cell death, which corresponded to a lack of GSTP1 protein re-expression. We have shown that GSTP1 DNA methylation and protein expression status is correlated with DNMTi treatment response in prostate cancer cells. Since GSTP1 is methylated in nearly all prostate cancers, our results warrant its testing as a marker of epigenetic therapy response in future clinical trials. We conclude that the DNA methylation and protein expression status of GSTP1 are good indicators of DNMTi efficacy.

The mechanisms underlying androgen receptor (AR)-mediated progression of prostate cancer following androgen ablation have yet to be fully determined. On this basis we screened naturally occurring mutants of human AR for hormone independent activity using a yeast model system. An initial screen of 43 different mutants revealed that ARs having a Leu701His mutation (ARL701H) exhibited hormone-independent activation of a lacZ reporter gene. The ARL701H mutant bound dihydrotestosterone to a similar extent as did wild type AR, although its ability to be induced by hormone for transactivation was reduced substantially. Subsequent studies focused on the dependence of ARL701H on molecular chaperones for folding to the active state. We found that ARL701H was highly dependent on Hsp90 for its hormone independent activation, suggesting that this chaperone functions in ARL701H folding. However, the mutant did not respond specifically to increased levels of FKBP52, suggesting that this chaperone functions at the hormone-dependent activation stage in the folding process. Further studies of ARL701H in PC3 cells suggested that this mutant is prohibited from hormone-independent transactivation in mammalian cells. However, basal expression of a reporter gene by ARL701H was not impaired by the presence of 17-allylamino-17-demethoxygeldanamycin as was wild type AR, suggesting differential interactions of these receptors with molecular chaperones in animal cells.

Background

Both food insufficiency and HIV infection are major public health problems in sub-Saharan Africa, yet the impact of food insufficiency on HIV risk behavior has not been systematically investigated. We tested the hypothesis that food insufficiency is associated with HIV transmission behavior.

Methods and Findings

We studied the association between food insufficiency (not having enough food to eat over the previous 12 months) and inconsistent condom use, sex exchange, and other measures of risky sex in a cross-sectional population-based study of 1,255 adults in Botswana and 796 adults in Swaziland using a stratified two-stage probability design. Associations were examined using multivariable logistic regression analyses, clustered by country and stratified by gender. Food insufficiency was reported by 32% of women and 22% of men over the previous 12 months. Among 1,050 women in both countries, after controlling for respondent characteristics including income and education, HIV knowledge, and alcohol use, food insufficiency was associated with inconsistent condom use with a nonprimary partner (adjusted odds ratio [AOR] 1.73, 95% confidence interval [CI] 1.27–2.36), sex exchange (AOR 1.84, 95% CI 1.74–1.93), intergenerational sexual relationships (AOR 1.46, 95% CI 1.03–2.08), and lack of control in sexual relationships (AOR 1.68, 95% CI 1.24–2.28). Associations between food insufficiency and risky sex were much attenuated among men.

Conclusions

Food insufficiency is an important risk factor for increased sexual risk-taking among women in Botswana and Swaziland. Targeted food assistance and income generation programs in conjunction with efforts to enhance women's legal and social rights may play an important role in decreasing HIV transmission risk for women.

In a cross-sectional study, Sheri Weiser and colleagues found that food insufficiency was an important risk factor for increased sexual risk-taking in women in Botswana and Swaziland.

Editors' Summary

Background.

For people in sub-Saharan Africa, insufficient food for their daily needs and infection with the human immunodeficiency virus (HIV; the cause of acquired immunodeficiency syndrome or AIDS) are inextricably linked and major causes of illness and death. By reducing the number of healthy adults in the region, HIV/AIDS has decreased food production so fewer people have secure access to sufficient food for a healthy life—many are subject to “food insecurity.” Because good nutrition is essential for a strong immune system, food insecurity increases the likelihood that people exposed to HIV become infected with the virus and reduces their ability to remain healthy after infection. Consequently, more people succumb to HIV/AIDS and food insecurity increases. To break this vicious cycle, UNAIDS (the Joint United Nations Programme on HIV/AIDS) and other international bodies have suggested a move towards integrated food security programs and HIV/AIDS prevention and treatment programs wherever possible.

Why Was This Study Done?

Integrated food and HIV/AIDS programs might also be beneficial for another reason. HIV is usually spread through unprotected sex with an infected partner and it is thought that a lack of food increases sexual risk taking, particularly among poor women. These women have little control over food supplies but are expected to feed their children and other members of the household (such as elders). To do this, they may sell sex or become sexually involved with men of a different generation, both of which put them at risk of HIV. In addition, they are rarely able to demand that their partners use condoms or to control when they have sex. In this study, the researchers have examined how food insufficiency affects sexual risk taking among men and women in Swaziland and Botswana. These two countries have the highest HIV infection rates in the world—one in three adults in Swaziland and one in four in Botswana are infected—and in both countries many people are extremely poor.

What Did the Researchers Do and Find?

The researchers interviewed more than 2,000 randomly selected adults from Botswana and Swaziland using a standard questionnaire. This included general questions about the participants (for example, age and marital status) and questions about food insufficiency (defined as not having had enough food to eat over the previous 12 months) and risky sexual behaviors—for example, sex exchange (selling or paying for sex) and inconsistent condom use—over the same period. Nearly one in three women and one in four men reported food insufficiency. After allowing for variables such as education and income, women in both countries who reported food insufficiency were nearly twice as likely to have used condoms inconsistently with a non-regular partner or to have sold sex as women who had had sufficient food. They were also more likely to have had intergenerational sexual relationships and to report a lack of control in sexual relationships. Among men, food insufficiency was weakly associated with inconsistent condom use but not with other risky sexual behaviors.

What Do These Findings Mean?

Food insufficiency is associated with multiple (often interdependent) risky sexual practices among women in Botswana and Swaziland. These results may not hold for other countries and may be limited by the definition of food insufficiency used in the study and by participants failing to remember or report all instances of risky behavior or food insufficiency that occurred during the previous year. Nevertheless, the findings strongly suggest that protecting and promoting access to food may decrease vulnerability of women in sub-Saharan Africa to HIV infection. Improved food security might be achieved through targeted food assistance and by supporting women's subsistence farming and other means of food production. Such programs would also need to enhance women's legal and social rights so that they have more control over food supplies as well as their sexual lives.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040260.

The Food and Agriculture Organization of the United Nations Special Programme for Food Security (in several languages)

HIV InSite, comprehensive and up-to-date information on all aspects of HIV/AIDS from the University of California San Francisco

UNAIDS (Joint United Nations Programme on HIV/AIDS) fact sheet on nutrition, food security, and HIV/AIDS

HIV and AIDS in Swaziland and Botswana, information provided by Avert, an international AIDS charity

The IMAGE Study, an example of a research initiative that is investigating the potential role of poverty alleviation and women's empowerment in reducing HIV incidence in South Africa