Better Viral Control despite Higher CD4+ T Cell Activation during Acute HIV-1 Infection in Zambian Women Is Linked to the Sex Hormone Estradiol.

The influence of biological sex on disease progression in HIV-1-infected individuals has been focused on the chronic stage of infection, but little is known about how sex differences influence acute HIV-1 infection. We observed profound differences in viral load and CD4+ T cell activation from the earliest time points in men and women in a Zambian heterosexual acute infection cohort. Women exhibited a >2-fold higher rate of CD4+ T cell loss despite significantly lower viral loads (VL) than men. The importance of studying acute infection was highlighted by the observation that very early in infection, women exhibited significantly higher levels of CD4+ T cell activation, a difference that was lost over the first 3 years of infection as activation in men increased. In women, activation of CD4+ T cells in the acute phase was significantly correlated with plasma levels of 17ß-estradiol (E2). However, unlike in men, higher CD4+ T cell activation in women was not associated with higher VL. In contrast, a higher E2 level in early infection was associated with lower early and set-point VL in women. We attribute this to an inhibitory effect of estradiol on virus replication, which we were able to observe with relevant transmitted/founder viruses in vitro Thus, estradiol plays a key role in defining major differences between men and women during early HIV-1 infection by contributing to both viral control and CD4+ T cell loss, an effect that extends into the chronic phase of the disease.IMPORTANCE Previous studies have identified sex-specific differences during chronic HIV-1 infection, but little is known about sex differences in the acute phase, or how disparities in the initial response to the virus may affect disease. We demonstrate that restriction of viral load in women begins during acute infection and is maintained into chronic infection. Despite this, women exhibit more rapid CD4+ T cell loss than men. These profound differences are influenced by 17ß-estradiol, which contributes both to T cell activation and to reduced viral replication. Thus, we conclude that estradiol plays a key role in shaping responses to early HIV-1 infection that influence the chronic phase of disease.

Estimation of HIV-testing rates to maximize early diagnosis-derived benefits at the individual and population level.

BACKGROUND: In HIV infection, initiation of treatment is associated with improved clinical outcom and reduced rate of sexual transmission. However, difficulty in detecting infection in early stages impairs those benefits. We determined the minimum testing rate that maximizes benefits derived from early diagnosis. METHODS: We developed a mathematical model of HIV infection, diagnosis and treatment that allows studying both diagnosed and undiagnosed populations, as well as determining the impact of modifying time to diagnosis and testing rates. The model's external consistency was assessed by estimating time to AIDS and death in absence of treatment as well as by estimating age-dependent mortality rates during treatment, and comparing them with data previously reported from CASCADE and DHCS cohorts. RESULTS: In our model, life expectancy of patients diagnosed before 8 years post infection is the same as HIV-negative population. After this time point, age at death is significantly dependent on diagnosis delay but initiation of treatment increases life expectancy to similar levels as HIV-negative population. Early mortality during HAART is dependent on treatment CD4 threshold until 6 years post infection and becomes dependent on diagnosis delay after 6 years post infection. By modifying testing rates, we estimate that an annual testing rate of 20% leads to diagnosis of 90% of infected individuals within the first 8.2 years of infection and that current testing rate in middle-high income settings stands close to 10%. In addition, many differences between low-income and middle-high incomes can be predicted by solely modifying the diagnosis delay. CONCLUSIONS: To increase testing rate of undiagnosed HIV population by two-fold in middle-high income settings will minimize early mortality during initiation of treatment and global mortality rate as well as maximize life expectancy. Our results highlight the impact of achieving early diagnosis and the importance of strongly work on improving HIV testing rates.

Drug resistance mutations in HIV pol sequences from Argentinean patients under antiretroviral treatment: subtype, gender, and age issues.

We studied drug resistance mutations (DRMs) in 2623 pol sequences. Out of 94,828 amino acid substitutions that were detected, 8749 corresponded to nucleoside reverse transcriptase inhibitor (NRTI), 3765 to nonnucleoside reverse transcriptase inhibitor (NNRTI), and 7141 to protease inhibitor (PI) resistance-associated mutations. The most common DRMs were L10I, I54V, L90M, V82A, A71V, L10V, M46I, M184V, M41L, T215Y, D67N, L210W, K70R, N348I, V118I, K103N, Y181C, G190A, K101E, V108I, L100I, V90I, K101Q, and A98G. As expected, DRMs frequencies depended on viral genotype. The amounts of NRTI and PI resistance mutations among B and BF sequences from children were higher than among sequences from adults. The frequencies of PI and NRTI resistance mutations among B and BF sequences from adult men were higher than among sequences from women. Some of these observations can be explained in light of the available epidemiological information, but some cannot, indicating that further studies are needed to understand the antiretroviral resistance epidemics in Argentina.

Stable human T-cell lymphotropic virus type 1 (HTLV-1) subtype a/subgroup a endemicity in Amerindians from Northwest Argentina: a health problem to be resolved.

Jujuy province, in Northwest Argentina, is known to be endemic for HTLV-1 infection. Moreover, foci of HTLV-1 associated pathologies have also been described in this region. To gain an insight into the current situation of HTLV-1/2 in this endemic area, a seroprevalence and phylogenetic study was performed among a Kolla community from Abra Pampa city and surroundings. Out of 112 individuals, 11 (9.8%) were confirmed as HTLV-1 positive and no HTLV-2 infection was detected. The phylogenetic analysis of the LTR region showed that all the HTLV-1 sequences belonged to the Cosmopolitan subtype a/transcontinental subgroup A, and were closely related to reference sequences from Peru, Argentina, and the South of Brazil (P = 0.82). Considering the cultural and historical features of this community and in spite of the mandatory detection of anti-HTLV-1/2 antibodies in blood banks since 2005, it would be important to implement new public health measures focused on decreasing HTLV-1 transmission in this endemic area.

Divergent strains of human T-lymphotropic virus type 1 (HTLV-1) within the Cosmopolitan subtype in Argentina.

HTLV-1 Cosmopolitan subtype Transcontinental subgroup A has been described among aboriginal communities from the northwest endemic area of Argentina. Moreover, Transcontinental subgroup A and the Japanese subgroup B were reported among blood donors from the nonendemic central region of the country. We carried out the first HTLV-1 phylogenetic study in individuals residing in Buenos Aires capital city. Phylogenetic analysis performed on the LTR region showed that all 44 new strains clustered within the Cosmopolitan subtype, with 42 (95.4%) belonging to Transcontinental subgroup A. Of them, 20 (45.5%) strains grouped in the large Latin American cluster and 4 (9.1%) in the small Latin American cluster. The majority of them belonged to individuals of nonblack origin, grouped with Amerindian strains. Three (6.8%) were closely related to South African references and two monophyletic clusters including only HIV/HTLV-1 coinfected individuals were observed. Interestingly, two (4.5%) new sequences (divergent strains) branched off from all five known Cosmopolitan subgroups in a well-supported clade. In summary, these findings show that HTLV-1 Cosmopolitan subtype Transcontinental subgroup A is infecting residents of Buenos Aires, a nonendemic area of Argentina, and confirm the introduction of divergent strains in the country.