To examine the hormonal and immunological mechanisms that mediate sex differences in susceptibility to malaria infection, intact and gonadectomized (gdx) C57BL/6 mice were inoculated with Plasmodium chabaudi AS-infected erythrocytes, and the responses to infection were monitored. In addition to reduced mortality, intact females recovered from infection-induced weigh loss and anemia faster than intact males. Expression microarrays and real-time reverse transcription-PCR revealed that gonadally intact females exhibited higher expression of interleukin-10 (IL-10), IL-15R␣, IL-12R␤, Gadd45␥, gamma interferon (IFN-␥), CCL3, CXCL10, CCR5, and several IFN-inducible genes in white blood cells and produced more IFN-␥ than did intact males and gdx females, with these differences being most pronounced during peak parasitemia. Intact females also had higher anti-P. chabaudi immunoglobulin G (IgG) and IgG1 responses than either intact males or gdx females. To further examine the effector mechanisms mediating sex differences in response to P. chabaudi infection, responses to infection were compared among male and female wild-type (WT), T-cell-deficient (TCR␤␦ ؊/؊ ), B-cell-deficient (MT), combined T-and B-cell-deficient (RAG1), and IFN-␥ knockout (IFN-␥ ؊/؊ ) mice. Males were 3.5 times more likely to die from malaria infection than females, with these differences being most pronounced among TCR␤␦ ؊/؊ , MT, and RAG1 mice. Male mice also exhibited more severe weight loss, anemia, and hypothermia, and higher peak parasitemia than females during infection, with WT, RAG1, TCR␤␦ ؊/؊ , and MT mice exhibiting the most pronounced sexual dimorphism. The absence of IFN-␥ reduced the sex difference in mortality and was more detrimental to females than males. These data suggest that differential transcription and translation of IFN-␥, that is influenced by estrogens, may mediate sex differences in response to malaria.Males are more susceptible to many protozoan infections than females and field and laboratory studies link increased susceptibility to infection with circulating steroid hormones (17,18,39). One genus of protozoan parasites that causes a pronounced sexual dimorphism in vertebrate hosts is Plasmodium. Among humans, although the incidence of infection is often similar between the sexes (see references 51 and 52), sex differences in the intensity of infection are reported in which men have higher parasitemia than women (23, 32, 52). The observation that P. falciparum (i.e., a human malaria parasite) density increases at puberty in men, but not in women, suggests that circulating sex steroids may influence this outcome (23).Studies of rodent malarias have confirmed that males are more likely to die after blood-stage malaria infection than are females (2,3,(54)(55)(56)

This work was supported in part by a research grant to Dilworth, Mercier, and Borrego from the American Society of Health-System Pharmacists Foundation. Klein and Pinkerton were supported in part by grants T32-MH19985 and P30-MH52776, respectively, from the National Institute of Mental Health. No funding bodies had any role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Health Resources and Services Administration. The authors have no conflicts of interest to disclose. Study concept and design were contributed primarily by Dilworth, Mercier, and Borrego, along with the other authors. Dilworth took the lead in data collection, along with Pinkerton, Klein, Mercier, and Jakeman. Data interpretation was performed by Dilworth and Pinkerton, along with the other authors. The manuscript was written by Dilworth, Klein, and Jakeman, with assistance from the other authors, and revised by Dilworth, Jakeman, and Klein, with assistance from the other authors. The results from this study were presented in part at the 2015 United States Conference on AIDS in Washington, DC, on September 10-13, 2015.

Background Nearly half of people with HIV in the United States are 50 years or older, and this proportion is growing. Between 2012 and 2016, the largest percent increase in the prevalence rate of HIV was among people aged 65 and older, the eligibility age for Medicare coverage for individuals without a disability or other qualifying condition. Previous work suggests that older people with HIV may have higher rates of chronic conditions and develop them more rapidly than older people who do not have HIV. This study compared the health status of older people with HIV with the older US population not living with HIV by comparing: (1) mortality; (2) prevalence of certain conditions, and (3) incidence of these conditions with increasing age. Methods and findings We used a sample of Medicare beneficiaries aged 65 and older from the Medicare Master Beneficiary Summary File for the years 2011 to 2016, including 100% of individuals with HIV (N = 43,708), as well as a random 1% sample of individuals without diagnosed HIV (N = 1,029,518). We conducted a survival analysis using a Cox proportional hazards model to assess mortality and to determine the need to adjust for differential mortality in our analyses of the incidence of certain chronic conditions. These results showed that Medicare beneficiaries living with HIV have a significantly higher hazard of mortality compared to older people without diagnosed HIV (3.6 times the hazard). We examined the prevalence of these conditions using logistic regression analysis and found that people with HIV have a statistically significant higher odds of depression, chronic kidney disease, chronic obstructive pulmonary disease (COPD), osteoporosis, hypertension, ischemic heart disease, diabetes, chronic hepatitis, end-stage liver disease, lung cancer, and colorectal cancer. To look at the rate at which older people are diagnosed with conditions as they age, we used a Fine-Gray competing risk model and showed that for individuals without diagnosis of a given condition at age 65, the future incidence of that condition over the remaining study period was higher for people with HIV even after adjusting for differential hazard of mortality and for other demographic characteristics. Many of these results also varied by personal characteristics including Medicaid dual enrollment, sex, and race and ethnicity, as well as by condition. Conclusions Increasing access to care and improving health outcomes for people with HIV is a critical goal of the National HIV/AIDS Strategy 2020. It is important for clinicians and policymakers to be aware that despite significant advances in the treatment and care of people with HIV, older people with HIV have a higher odds of having multiple chronic conditions at any point in time, a higher incidence of new diagnoses of these conditions over time, and a higher hazard of mortality than Medicare beneficiaries without HIV.

BackgroundIn the United States, approximately one-fifth of transgender women are living with HIVnearly one-half of Black/African American (Black) transgender women are living with HIV. Limited data are available on HIV-related clinical indicators among transgender women. This is because of a lack of robust transgender data collection and research, especially within demographic subgroups. The objective of this study was to examine retention in care and viral suppression among transgender women accessing the Health Resources and Services Administration's (HRSA) Ryan White HIV/AIDS Program (RWHAP)-supported HIV care, compared with cisgender women and cisgender men. Methods and findingsWe assessed the association between gender (cisgender or transgender) and (1) retention in care and (2) viral suppression using 2016 client-level RWHAP Services Report data. Multivariable modified Poisson regression models adjusting for confounding by age, race, health care coverage, housing, and poverty level, overall and stratified by race/ethnicity, were used to calculate adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs). In 2016, the RWHAP served 6,534 transgender women (79.8% retained in care, 79.0% virally suppressed), 143,173 cisgender women (83.7% retained in care, 84.0% virally suppressed), and 382,591 cisgender men (81.0% retained in care, 85.9% virally suppressed). Black transgender women were less likely to be retained in care than Black cisgender women (aPR: 0.95, 95% CI: 0.92-0.97, p < 0.001). Black transgender women were also less likely to reach viral suppression than Black cisgender women (aPR: 0.55, 95%I CI: 0.41-0.73, p < 0.001) and Black cisgender men (aPR: 0.55, 95% CI: 0.42-0.73, p < 0.001).

Background Previous data from our laboratory suggest that gonadally intact C57BL/6 male mice are more likely than their female counterparts to die from Plasmodium chabaudi infection, to recover more slowly from weight loss and hematocrit loss, and to have reduced interferon-gamma (IFN-γ) and interleukin (IL)-10 responses. Removal of the ovaries, and hence, the primary production of sex steroids in females, reverses these differences. Objective We hypothesized that sex differences in response to P. chabaudi may be mediated by differential synthesis of IFN-γ and IL-10 that is influenced by estrogen, progesterone, or both. Methods C57BL/6 female mice ( n = 200; n = 10/time point/treatment/experiment) were ovariectomized (OVX) and implanted with either a 21-day controlled-release pellet containing 0.1 mg of 17β-estradiol (E2), 10 mg of progesterone (P4), 0.1 mg of E2 plus 10 mg of P4, or cholesterol (placebo). Females were inoculated with 106 P. chabaudi-infected erythrocytes. Body mass, body temperature, hematocrit, parasitemia, cytokine production, and antibody responses were monitored 0, 3, 5, 7, 10, 14, and 21 days postinoculation. Results Administration of E2, either alone or in combination with P4, mitigated infection-induced weight loss, hematocrit loss, and hypothermia, as compared with females receiving placebo pellets (P < 0.05 in each case). Hormone treatment did not affect levels of parasitemia. Females administered E2 alone or in combination with P4 produced 50–150 times more IFN-γ and IL-10 during peak parasitemia than did females implanted with pellets containing either P4 alone or placebo (P < 0.05 in each case). Exposure to E2, either alone or in combination with P4, increased anti-P. chabaudi immunoglobulin G (IgG1) responses and the ratio of IgG1 to IgG2c (P < 0.05 in each case). Conclusion This animal study suggests that physiological levels of estrogen, rather than progesterone, enhance immunity and, possibly, protect females from disease symptoms during malaria infection.