Kathleen R. Page

The expanding realm of heterologous immunity: friend or foe?

Antecedent or current infections can alter the immunopathologic outcome of a subsequent unrelated infection. Immunomodulation by co‐infecting pathogens has been referred to as ‘heterologous immunity’ and has been postulated to play a role in host susceptibility to disease, tolerance to organ transplant, and autoimmune disease. The effect of various infections on heterologous immune responses has been well studied in the context of shared epitopes and cross‐reactive T cells. It has been shown that prior infections can modulate protective immunity and immunopathology by forming a pool of memory T cells that can cross‐react with antigens from heterologous organisms or through the generation of a network of regulatory cells and cytokines. While it is not feasible to alter a hosts history of prior infection, understanding heterologous immune responses in the context of simultaneous unrelated infections could have important therapeutic implications. Here, we outline key evidence from animal and human studies demonstrating the effect of heterologous immunity on the outcome of disease. We briefly review the role of T cells, but expand our discussion to explore other immune mechanisms that may modulate the response to concurrent active infections. In particular, we underscore the role of the innate immune system, polarized responses and regulatory mechanisms on heterologous immune responses.

Unstimulated Primary CD4+ T Cells from HIV-1-Positive Elite Suppressors Are Fully Susceptible to HIV-1 Entry and Productive Infection

ABSTRACT Elite controllers or suppressors (ES) are a group of HIV-1-infected individuals who maintain viral loads below the limit of detection of commercial assays for many years. The mechanisms responsible for this remarkable control are under intense study, with the hope of developing therapeutic vaccines effective against HIV-1. In this study, we addressed the question of the intrinsic susceptibility of ES CD4+ T cells to infection. While we and others have previously shown that CD4+ T cells from ES can be infected by HIV-1 isolates in vitro, these studies were confounded by exogenous activation and in vitro culture of CD4+ T cells prior to infection. In order to avoid the changes in chemokine receptor expression that have been associated with such exogenous activation, we infected purified CD4+ T cells directly after isolation from the peripheral blood of ES, viremic patients, and uninfected donors. We utilized a green fluorescent protein (GFP)-expressing proviral construct pseudotyped with CCR5-tropic or CXCR4-tropic envelope to compare viral entry using a fluorescence resonance energy transfer-based, single-round virus-cell fusion assay. The frequency of productive infection was also compared by assessing GFP expression. CD4+ T cells from ES were as susceptible as or more susceptible than cells from viremic patients and uninfected donors to HIV-1 entry and productive infection. The results of this physiological study strongly suggest that differences in HIV-1 entry and infection of CD4+ T cells alone cannot explain the elite control of viral replication.

Mycobacterium-Induced Potentiation of Type 1 Immune Responses and Protection against Malaria Are Host Specific

ABSTRACT Malaria and tuberculosis are endemic in many regions of the world, and coinfection with the two pathogens is common. In this study, we examined the effects of long- and short-term infection with Mycobacterium tuberculosis on the course of a lethal form of murine malaria in resistant (C57BL/6) and susceptible (BALB/c) mice. C57BL/6 mice coinfected with M. tuberculosis CDC1551 and Plasmodium yoelii 17XL had a lower peak parasitemia and increased survival compared to mice infected with P. yoelii 17XL alone. Splenic microarray analysis demonstrated potentiation of type 1 immune responses in coinfected C57BL/6 mice, which was especially prominent 5 days after infection with P. yoelii 17XL. Splenocytes from coinfected C57BL/6 mice produced higher levels of gamma interferon (IFN-γ) and tumor necrosis factor alpha than splenocytes from mice infected with either pathogen alone. Interestingly, mycobacterium-induced protection against lethal P. yoelii is mouse strain specific. BALB/c mice were significantly more susceptible than C57BL/6 mice to infection with P. yoelii 17XL and were not protected against lethal malaria by coinfection with M. tuberculosis. In addition, M. tuberculosis did not augment IFN-γ responses in BALB/c mice subsequently infected with P. yoelii 17XL. These data indicate that M. tuberculosis-induced potentiation of type 1 immune responses is associated with protection against lethal murine malaria.

Transforming growth factor-β1 in plasma and liver of children with liver disease

Although several liver diseases of childhood, particularly biliary atresia(BA) and cystic fibrosis (CF) liver disease (CFLD) are characterized by hepatic fibrosis, the pathogenesis of this process is incompletely understood. The cytokine transforming growth factor-β1 (TGF-β1) has been implicated in hepatic fibrosis in experimental animals, in which both the hepatic expression and plasma concentration of this cytokine are increased. The objective of our study was to determine whether there are similar alterations of TGF-β1 in patients with hepatic fibrosis secondary to either BA and/or CFLD. The study design was as follows. In study 1, plasma TGF-β1 was assessed by ELISA in 9 children with BA undergoing liver transplantation, 11 patients with CFLD, and appropriate control subjects. In study 2, hepatic expression of TGF-β1 protein (assessed immunohistochemically) and hepatic fibrosis were scored semiquantitatively, on a 1-3 scale, by blinded investigators, in archival liver biopsy specimens from 10 children with BA, 10 with CFLD, and from 10 older children with normal hepatic histology, as well as in 4 patients with liver diseases of various etiologies. Simultaneous plasma and liver TGF-β1 studies were performed in 8 patients with liver disease. Results were as follows. Plasma TGF-β1 values were inversely correlated with age in healthy subjects(r = -0.54, p < 0.0001). The plasma TGF-β1 protein of children with BA was decreased (13 ± 2 ng/mL) compared with values for healthy children (42 ± 6 ng/mL, n = 10,p < 0.005). Similarly, the plasma TGF-β1 concentration in patients with CFLD was also decreased compared with values for children with CF and normal serum liver profiles (n = 14) (2 ± 1 ng/mL versus 12 ± 1, p < 0.05). However, the plasma TGF-β1 concentration was increased in two patients with other types of liver disease. The hepatic expression of TGF-β1 was increased in the presence of hepatic fibrosis in all types of liver diseases studied. Forty-six percent of patients had both marked hepatic fibrosis and marked TGF-β1 labeling; 86% of samples without fibrosis showed no TGF-β1 labeling, p = 0.007. In conclusion, these studies have established the association of hepatic TGF-β1 protein and hepatic fibrosis in several common liver diseases of childhood. Our data also suggest that, in children, plasma TGF-β1 does not appear to be a useful marker of hepatic expression of this cytokine.

Neisseria gonorrhoeae and Chlamydia trachomatis among Women Reporting Extragenital Exposures

Background The Centers for Disease Control and Prevention recommends pharyngeal screening of Neisseria gonorrhoeae (GC) and rectal screening of GC and Chlamydia trachomatis (CT) in HIV-infected and at-risk men who have sex with men (MSM). There are currently no recommendations to routinely screen women at extragenital sites. We define the prevalence of extragenital GC and CT in women attending 2 urban sexually transmitted disease clinics in Baltimore City and compare it with the prevalence of extragenital infections in MSM and men who have sex with women. Methods All patients who reported extragenital exposures in the preceding 3 months, who presented for care between June 1, 2011, and May 31, 2013, and who were tested for GC and CT using nucleic acid amplification tests at all sites of exposure were included in the analyses. We used logistic regression models to identify risk factors for extragenital infections. Results A total of 10,389 patients were included in this analysis (88% African American; mean age, 29 years; 42% women; 7% MSM; 2.5% HIV infected). The prevalence estimates of any extragenital GC and CT were as follows: 2.4% GC and 3.7% CT in women, 2.6% GC and 1.6% CT in men who have sex with women, and 18.9% GC and 11.8% CT in MSM. Among women, 30.3% of GC infections and 13.8% of CT infections would have been missed with urogenital-only testing. Unlike MSM, age ⩽18 years was the strongest predictor of extragenital infections in women. Conclusions Although the prevalence of extragenital gonorrhea and chlamydia is highest in MSM, a significant number of GC and CT infections in young women would be missed with genital-only testing. Cost-effectiveness analyses are needed to help inform national guidelines on extragenital screening in young women.

Sexually Transmitted Infection Prevalence and Behavioral Risk Factors among Latino and Non-Latino Patients Attending the Baltimore City STD Clinics

Background: Many studies have evaluated factors influencing sexually transmitted diseases (STD)/HIV disparities between black and white populations, but fewer have explicitly included Latinos for comparison. Methods: We analyzed demographic and behavioral data captured in electronic medical records of patients first seen by a clinician in 1 of 2 Baltimore City public STD clinics between 2004 and 2007. Records from white, black, and Latino patients were included in the analysis. Results: There were significant differences between Latinos and other racial/ethnic groups for several behavioral risk factors studied, with Latino patients reporting fewer behavioral risk factors than other patients. Latinos were more likely to have syphilis, but less likely to have gonorrhea than other racial/ethnic groups. English-proficient Latina (female) patients reported higher rates of infection and behavioral risk factors than Spanish-speaking Latina patients. After adjustment for gender and behavioral risk factors, Spanish-speaking Latinas also had significantly less risk of sexually transmitted infections than did English-speaking Latinas. Conclusions: These results are consistent with other studies showing that acculturation (as measured by language proficiency) is associated with increases in reported sexual risk behaviors among Latinos. Future studies on sexual risk behavior among specific Latino populations, characterized by country of origin, level of acculturation, and years in the United States, may identify further risk factors and protective factors to guide development of culturally appropriate STD/HIV interventions.

Mycobacterium tuberculosis Complex Enhances Susceptibility of CD4 T Cells to HIV through a TLR2-Mediated Pathway

Among HIV-infected individuals, co-infection with Mycobacterium tuberculosis is associated with faster progression to AIDS. We investigated the hypothesis that M. bovis BCG and M. tuberculosis (Mtb complex) could enhance susceptibility of CD4+ cells to HIV infection. Peripheral blood mononuclear cells (PBMCs) collected from healthy donors were stimulated with M. bovis BCG, M. tuberculosis CDC1551 and M. smegmatis MC2155, and stimulated CD4+ cells were infected with R5-and X4-tropic single replication-competent pseudovirus. CD4+ cells stimulated with Mtb complex showed enhanced infection with R5- and X4-tropic HIV, compared to unstimulated cells or cells stimulated with M. smegmatis (p<0.01). Treatment with TLR2 siRNA reversed the increased susceptibility of CD4+ cells with R5- and X4-tropic virus induced by Mtb complex. These findings suggest that TB infection and/or BCG vaccination may be a risk factor for HIV acquisition.

HIV Testing Behaviors Among Latinos in Baltimore City

In the US, HIV disproportionately affects Latinos who often present late in the disease. Baltimore has seen a recent rapid growth in its Latino population paralleled by an increasing impact of HIV/AIDS among Latinos. From 2009 to 2010, we performed a cross-sectional survey of Latinos accessing the Baltimore City Health Department (BCHD) Latino Outreach services to assess self-report of previous HIV testing, with particular attention to migration history and risk behaviors. Of 247 Latinos (46% male) accessing BCHD outreach services, 96% were foreign-born. Self-perceived HIV risk was not associated with actual risk behaviors or HIV testing. In multivariate models, previous HIV testing was correlated with knowledge of HIV transmission modes and knowing that a person with HIV can appear healthy. Consistent with CDC recommendations, HIV screening among Latino immigrants should not be limited to individuals with self-perceived risk for HIV. Promoting key pieces of HIV knowledge may improve HIV testing behaviors.

Public health clinic-based hepatitis C testing and linkage to care in baltimore

Testing and linkage to care are important determinants of hepatitis C virus (HCV) treatment effectiveness. Public health clinics serve populations at high risk of HCV. We investigated their potential to serve as sites for HCV testing, initiation of and linkage to HCV care. Cross‐sectional study of patients accessing sexually transmitted infection (STI) care at the Baltimore City Health Department (BCHD) STI clinics, from June 2013 through April 2014 was conducted. Logistic regression was used to assess factors associated with HCV infection and specialist linkage to care. Between 24 June 2013 and 15 April 2014, 2681 patients were screened for HCV infection. Overall, 189 (7%) were anti‐HCV positive, of whom 185 (98%) received follow‐up HCV RNA testing, with 155 (84%) testing RNA positive. Of 155 RNA‐positive individuals, 138 (89%) returned to the STI clinic for HCV RNA results and initial HCV care including counselling regarding transmission and harm reduction in alcohol, and 132 (85%) were referred to a specialist for HCV care. With provision of patient navigation services, 81 (52%) attended an offsite HCV specialist appointment. Alcohol use and lack of insurance coverage were associated with lower rates of specialist linkage (OR 0.4 [95% CI 0.1–0.9] and OR 0.4 [95% CI 0.1–0.9], respectively). We identified a high prevalence of HCV infection in BCHD STI clinics. With availability of patient navigation services, a large proportion of HCV‐infected patients linked to off‐site specialist care.

Unique Aspects of the Care of HIV-Positive Latino Patients Living in the United States

Latinos are disproportionately affected by HIV, with a higher risk of infection and a delayed presentation to care as compared to non-Hispanic whites. Over the last decade many Latinos, especially foreign-born migrants, have settled in regions of the country with historically low Latino representation. Therefore, clinicians who care for HIV-infected patients are likely to encounter Latino patients, regardless of their practice location. Providing optimal care to this population may be especially challenging for clinicians practicing in areas of newer Latino expansion, where culturally appropriate services may be sparse. In this article, we argue that an understanding of the HIV epidemic among Latinos requires an appreciation of the diversity and heterogeneity of the Latino population in the United States. We also review unique clinical aspects of HIV care among Latinos, including manifestation of co-infections with pathogens endemic in Latin America but rare in the United States.