Reduced Simian Immunodeficiency Virus Replication in Macrophages of Sooty Mangabeys Is Associated with Increased Expression of Host Restriction Factors.

UNLABELLED: Macrophages are target cells of HIV/SIV infection that may play a role in AIDS pathogenesis and contribute to the long-lived reservoir of latently infected cells during antiretroviral therapy (ART). In previous work, we and others have shown that during pathogenic SIV infection of rhesus macaques (RMs), rapid disease progression is associated with high levels of in vivo macrophage infection. In contrast, during nonpathogenic SIV infection of sooty mangabeys (SMs), neither spontaneous nor experimental CD4(+) T cell depletion results in substantial levels of in vivo macrophage infection. To test the hypothesis that SM macrophages are intrinsically more resistant to SIV infection than RM macrophages, we undertook an in vitro comparative assessment of monocyte-derived macrophages (MDMs) from both nonhuman primate species. Using the primary isolate SIVM949, which replicates well in lymphocytes from both RMs and SMs, we found that infection of RM macrophages resulted in persistent SIV-RNA production while SIV-RNA levels in SM macrophage cultures decreased 10- to 100-fold over a similar temporal course of in vitro infection. To explore potential mechanisms responsible for the lower levels of SIV replication and/or production in macrophages from SMs we comparatively assessed, in the two studied species, the expression of the SIV coreceptor as well as the expression of a number of host restriction factors. While previous studies showed that SM monocytes express lower levels of CCR5 (but not CD4) than RM monocytes, the level of CCR5 expression in MDMs was similar in the two species. Interestingly, we found that SM macrophages exhibited a significantly greater increase in the expression of tetherin (P = 0.003) and TRIM22 (P = 0.0006) in response to alpha interferon stimulation and increased expression of multiple host restriction factors in response to lipopolysaccharide stimulation and exposure to SIV. Overall, these findings confirm, in an in vitro infection system, that SM macrophages are relatively more resistant to SIV infection compared to RM macrophages, and suggest that a combination of entry and postentry restriction mechanisms may protect these cells from productive SIV infection. IMPORTANCE: This manuscript represents the first in vivo comparative analysis of monocyte-derived macrophages (MDMs) between rhesus macaques, i.e., experimental SIV hosts in which the infection is pathogenic and macrophages can be infected, and sooty mangabeys, i.e., natural SIV hosts in which the infection is nonpathogenic and macrophages are virtually never infected in vivo. This study demonstrates that mangabey-derived MDMs are more resistant to SIV infection in vitro compared to macaque-derived MDMs, and provides a potential explanation for this observation by showing increased expression of specific retrovirus restriction factors in mangabey-derived macrophages. Overall, this study is important as it contributes to our understanding of why SIV infection is nonpathogenic in sooty mangabeys while it is pathogenic in macaques, and is consistent with a pathogenic role for in vivo macrophage infection during pathogenic lentiviral infection.

Evaluating Facility Infrastructure for Prevention of Mother-to-Child Transmission of HIV-A 2015 Assessment of Major Delivery Hospitals in Atlanta, Georgia.

OBJECTIVE: Our goal was to evaluate the infrastructure of programs for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) in major delivery units in the Atlanta, Georgia, metropolitan statistical area and to assess the knowledge, attitude, and practice of providers in these facilities around PMTCT. METHODS: Hospital assessments and individual knowledge and practices were surveyed among 71 healthcare providers from March 2015 to March 2016 in 11 hospitals that deliver 40000 infants annually, which represents 70% of all deliveries in the Atlanta metropolitan statistical area. Included were questions about HIV testing for mother-infant pairs, test result turnaround times, policies and procedures for PMTCT, opt-out versus opt-in testing, availability of rapid point-of-care testing on labor and delivery units, and postnatal prophylaxis. RESULTS: Seventy-three percent (8 of 11) of the hospitals had limitations in their PMTCT infrastructure, and 36% (4 of 11) reported no standardized policies for care of HIV-infected women. Three labor and delivery units used opt-in HIV testing of women. Only 27% (3 of 11) of the hospitals reported nucleic acid testing of HIV-exposed infants. Oral zidovudine for infant prophylaxis was available in all the hospitals, but 64% (7 of 11) of them did not stock nevirapine. Fifty-nine percent (24 of 44) of the obstetricians did not routinely offer rapid testing at delivery without a third-trimester HIV test, and 78% (n = 32 of 41) of them did not offer testing at delivery if the woman declined antenatal testing. The facility with the most annual births in Georgia did not offer rapid testing at delivery for women with an unknown HIV status. CONCLUSION: We identified several limitations in PMTCT infrastructure that might have contributed to perinatal HIV transmissions. The need to address these healthcare gaps to eliminate mother-to-child transmission of HIV in the United States is urgent.

Early resolution of acute immune activation and induction of PD-1 in SIV-infected sooty mangabeys distinguishes nonpathogenic from pathogenic infection in rhesus macaques.

Primate lentiviruses are typically apathogenic in their evolutionarily coadapted host species but can be lethal when transferred to new host species. Why such infections are pathogenic in humans and rhesus macaques (RMs) but not in sooty mangabeys (SMs), a natural host, remains unclear. Studies of chronically infected animals point to the importance of diminished immune activation in response to the infection in SMs. In this study, we sought the causes and timing of the differences in immune activation in a comparative study of acute SIV infection in RMs and SMs. Surprisingly, we show that in acute infection immune activation is comparable in SMs and RMs but thereafter, SMs quickly resolve immune activation, whereas RMs did not. Early resolution of immune activation in SMs correlated with increased expression of PD-1 and with preservation of CD4(+) T cell counts and lymphatic tissue architecture. These findings point to early control of immune activation by host immunoregulatory mechanisms as a major determinant of the different disease outcomes in SIV infection of natural vs non-natural hosts.