Instruct: Given a scientific claim, retrieve documents that support or refute the claim.
Query: Continued HHV-8 transmission among MSM in San Francisco may be explained by urogenital contact.
CONTEXT Some studies have inferred that an epidemic of Kaposi sarcoma-associated herpesvirus (KSHV) infection in homosexual men in the United States occurred concurrently with that of human immunodeficiency virus (HIV), but there have been no direct measurements of KSHV prevalence at the beginning of the HIV epidemic. OBJECTIVES To determine the prevalence of KSHV infection in homosexual men in San Francisco, Calif, at the beginning of the HIV epidemic in 1978 and 1979 and to examine changes in prevalence of KSHV at time points from 1978 through 1996 in light of changes in sexual behavior. DESIGN, SETTING, AND PARTICIPANTS Analysis of a clinic-based sample (n = 398) derived from the San Francisco City Clinic Cohort (ages 18-66 years) (n = 2666 for analyses herein) and from population-based samples from the San Francisco Men's Health Study (MHS) (ages 25-54 years) (n = 825 and 252) and the San Francisco Young Men's Health Study (YMHS) (ages 18-29 years) (n = 428-976, and 557); behavioral studies were longitudinal and KSHV prevalence studies were cross-sectional. MAIN OUTCOME MEASURES Antibodies against KSHV and HIV; sexual behaviors. RESULTS The prevalence of KSHV infection in 1978 and 1979 was 26.5% of 235 (a random sample) overall (weighted for HIV infection) vs 6.9% (128/1842) for HIV in the San Francisco City Clinic Cohort sample. The prevalence of KSHV infection remained essentially unchanged between an MHS sample of 252 in 1984 and 1985 (29.6%) and a YMHS sample of 557 in 1995 and 1996 (26.4%), while HIV prevalence dropped from 49.5% of 825 in 1984 and 1985 (MHS) to 17.6% of 428 in 1992 and 1993 (YMHS). The proportion of men practicing unprotected receptive anal intercourse with 1 or more partners declined from 54% to 11% during the 1984 through 1993 period (MHS) with similar though slightly higher values in the YMHS in 1992 and 1993; whereas for unprotected oral intercourse it ranged between 60% and 90% in the 1984 through 1996 period (MHS and YMHS). CONCLUSIONS Infection with KSHV was already highly prevalent in homosexual men when the HIV epidemic began in San Francisco, and its prevalence has been maintained at a nearly constant level. Any declines in the incidence of Kaposi sarcoma do not appear to be caused by a decline in KSHV transmission.
Dendritic cells (DCs) are essential antigen-presenting cells for the induction of immunity against pathogens. However, HIV-1 spread is strongly enhanced in clusters of DCs and CD4(+) T cells. Uninfected DCs capture HIV-1 and mediate viral transfer to bystander CD4(+) T cells through a process termed trans-infection. Initial studies identified the C-type lectin DC-SIGN as the HIV-1 binding factor on DCs, which interacts with the viral envelope glycoproteins. Upon DC maturation, however, DC-SIGN is down-regulated, while HIV-1 capture and trans-infection is strongly enhanced via a glycoprotein-independent capture pathway that recognizes sialyllactose-containing membrane gangliosides. Here we show that the sialic acid-binding Ig-like lectin 1 (Siglec-1, CD169), which is highly expressed on mature DCs, specifically binds HIV-1 and vesicles carrying sialyllactose. Furthermore, Siglec-1 is essential for trans-infection by mature DCs. These findings identify Siglec-1 as a key factor for HIV-1 spread via infectious DC/T-cell synapses, highlighting a novel mechanism that mediates HIV-1 dissemination in activated tissues.
Health professionals and the public need to understand the natural history of human papillomavirus (HPV) infections of the cervix to best use the information provided by new molecular screening tests. We investigated outcomes of 800 carcinogenic HPV infections detected in 599 women at enrollment into a population-based cohort (Guanacaste, Costa Rica). For individual infections, we calculated cumulative proportions of three outcomes (viral clearance, persistence without cervical intraepithelial neoplasia grade 2 or worse [CIN2+], or persistence with new diagnosis of CIN2+) at successive 6-month time points for the first 30 months of follow-up. Cervical specimens were tested for carcinogenic HPV genotypes using an L1 degenerate-primer polymerase chain reaction method. Infections typically cleared rapidly, with 67% (95% confidence interval [CI] = 63% to 70%) clearing by 12 months. However, among infections that persisted at least 12 months, the risk of CIN2+ diagnosis by 30 months was 21% (95% CI = 15% to 28%). The risk of CIN2+ diagnosis was highest among women younger than 30 years with HPV-16 infections that persisted for at least 12 months (53%; 95% CI = 29% to 76%). These findings suggest that the medical community should emphasize persistence of cervical HPV infection, not single-time detection of HPV, in management strategies and health messages.
HIV-1 replication is concentrated within CD4(+) T cells in B cell follicles of secondary lymphoid tissues during asymptomatic disease. Limited data suggest that a subset of T follicular helper cells (TFH) within germinal centers (GC) is highly permissive to HIV-1. Whether GC TFH are the major HIV-1 virus-producing cells in vivo has not been established. In this study, we investigated TFH permissivity to HIV-1 ex vivo by spinoculating and culturing tonsil cells with HIV-1 GFP reporter viruses. Using flow cytometry, higher percentages of GC TFH (CXCR5(high)PD-1(high)) and CXCR5(+)programmed cell death-1 (PD-1)(low) cells were GFP(+) than non-GC TFH (CXCR5(+)PD-1(intermediate)) or extrafollicular (EF) (CXCR5(-)) cells. When sorted prior to spinoculation, however, GC TFH were substantially more permissive than CXCR5(+)PD-1(low) or EF cells, suggesting that many GC TFH transition to a CXCR5(+)PD-1(low) phenotype during productive infection. In situ hybridization on inguinal lymph node sections from untreated HIV-1-infected individuals without AIDS revealed higher frequencies of HIV-1 RNA(+) cells in GC than non-GC regions of follicle or EF regions. Superinfection of HIV-1-infected individuals' lymph node cells with GFP reporter virus confirmed the permissivity of follicular cells ex vivo. Lymph node immunostaining revealed 96% of CXCR5(+)CD4(+) cells were located in follicles. Within sorted lymph node cells from four HIV-infected individuals, CXCR5(+) subsets harbored 11-66-fold more HIV-1 RNA than CXCR5(-) subsets, as determined by RT PCR. Thus, GC TFH are highly permissive to HIV-1, but downregulate PD-1 and, to a lesser extent, CXCR5 during HIV-1 replication. These data further implicate GC TFH as the major HIV-1-producing cells in chronic asymptomatic HIV-1 infection.
HIV continues to spread globally, mainly through sexual contact. Despite advances in treatment and care, preventing transmission with vaccines or microbicides has proven difficult. A promising strategy to avoid transmission is prophylactic treatment with antiretroviral drugs before exposure to HIV. Clinical trials evaluating the efficacy of daily treatment with the reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) or Truvada (TDF plus emtricitabine) are under way. We hypothesized that intermittent prophylactic treatment with long-acting antiviral drugs would be as effective as daily dosing in blocking the earliest stages of viral replication and preventing mucosal transmission. We tested this hypothesis by intermittently giving prophylactic Truvada to macaque monkeys and then exposing them rectally to simian-human immunodeficiency virus (SHIV) once a week for 14 weeks. A simple regimen with an oral dose of Truvada given 1, 3, or 7 days before exposure followed by a second dose 2 hours after exposure was as protective as daily drug administration, possibly because of the long intracellular persistence of the drugs. In addition, a two-dose regimen initiated 2 hours before or after virus exposure was effective, and full protection was obtained by doubling the Truvada concentration in both doses. We saw no protection if the first dose was delayed until 24 hours after exposure, underscoring the importance of blocking initial replication in the mucosa. Our results show that intermittent prophylactic treatment with an antiviral drug can be highly effective in preventing SHIV infection, with a wide window of protection. They strengthen the possibility of developing feasible, cost-effective strategies to prevent HIV transmission in humans.
To prevent acquisition of HIV through oral sex, drugs used for preexposure prophylaxis (Prep) need to diffuse in saliva. We measured tenofovir (TFV) and emtricitabine (FTC) concentrations simultaneously in the plasma and saliva of 41 HIV-infected patients under stable antiretroviral treatment. Mean ratios of saliva/plasma concentration were 3% (±4%) and 86.9% (±124%) for TFV and FTC, respectively. Tenofovir disoproxil fumarate (TDF) should be used in combination with FTC to prevent oral acquisition of HIV.
The fly Musca sorbens Wiedemann (Diptera: Muscidae) apparently transmits Chlamydia trachomatis, causing human trachoma. The literature indicates that M. sorbens breeds predominantly in isolated human faeces on the soil surface, but not in covered pit latrines. We sought to identify breeding media of M. sorbens in a rural Gambian village endemic for trachoma. Test breeding media were presented for oviposition on soil-filled buckets and monitored for adult emergence. Musca sorbens emerged from human (6/9 trials), calf (3/9), cow (3/9), dog (2/9) and goat (1/9) faeces, but not from horse faeces, composting kitchen scraps or a soil control (0/9 of each). After adjusting for mass of medium, the greatest number of flies emerged from human faeces (1426 flies/kg). Median time for emergence was 9 (inter quartile range = 8-9.75) days post-oviposition. Of all flies emerging from faeces 81% were M. sorbens. Male and female flies emerging from human faeces were significantly larger than those from other media, suggesting that they would be more fecund and live longer than smaller flies from other sources. Female flies caught from children's eyes were of a similar size to those from human faeces, but significantly larger than those from other media. We consider that human faeces are the best larval medium for M. sorbens, although some breeding also occurs in animal faeces. Removal of human faeces from the environment, through the provision of basic sanitation, is likely to greatly reduce fly density, eye contact and hence trachoma transmission, but if faeces of other animals are present M. sorbens will persist.
Hepatitis C virus (HCV) is a leading cause of liver cancer and cirrhosis, and Egypt has possibly the highest HCV prevalence worldwide. In this article we use a newly developed Bayesian inference framework to estimate the transmission dynamics of HCV in Egypt from sampled viral gene sequences, and to predict the public health impact of the virus. Our results indicate that the effective number of HCV infections in Egypt underwent rapid exponential growth between 1930 and 1955. The timing and speed of this spread provides quantitative genetic evidence that the Egyptian HCV epidemic was initiated and propagated by extensive antischistosomiasis injection campaigns. Although our results show that HCV transmission has since decreased, we conclude that HCV is likely to remain prevalent in Egypt for several decades. Our combined population genetic and epidemiological analysis provides detailed estimates of historical changes in Egyptian HCV prevalence. Because our results are consistent with a demographic scenario specified a priori, they also provide an objective test of inference methods based on the coalescent process.
A small, isolated outbreak of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) due to dengue virus type 2 (DEN-2) was documented in Santiago de Cuba on the island of Cuba beginning in January 1997. There were 205 DHF/DSS cases, all in persons older than age 15 years. All but three had evidence of a prior dengue infection, with the only known opportunity being the islandwide dengue virus type 1 (DEN-1) epidemic of 1977-1979. Virtually complete clinical and laboratory surveillance of overt disease was achieved. From December 1997 to January 1998, a random, age-stratified serum sample was obtained from 1,151 persons in 40 residential clusters in Santiago. Sera were tested for DEN-1 and DEN-2 neutralizing antibodies. The prevalence of DEN-2 antibodies in children age 15 years and under, born after the 1981 DEN-2 epidemic, was taken as the 1997 DEN-2 infection rate. This was adjusted slightly to accommodate observed cases, resulting in an estimated infection rate of 4.3%. Dengue fever and DHF/DSS attack rates were calculated from estimated total primary and secondary DEN-2 infections. Only 3% of 13,116 primary infections were overt. The DHF/DSS attack rate for adults of all ages was 420 per 10,000 secondary DEN-2 infections.
Injection drug users (IDUs) are at increased risk for HIV, viral hepatitis, and tuberculosis, and making up more than a quarter of the incarcerated population in the United States. Methadone maintenance treatment of opiate addiction is highly effective at reducing drug use, drug-related criminal activity, and risk of HIV transmission. Recently released inmates are at particularly high risk for overdose and disease transmission. Linkage to methadone treatment immediately upon release from incarceration is a promising opportunity to combat disease transmission, facilitate reentry into the community, and reduce recidivism.
OBJECTIVE To determine whether the novel avian influenza H7N9 virus can transmit from person to person and its efficiency. DESIGN Epidemiological investigations conducted after a family cluster of two patients with avian H7N9 in March 2013. SETTING Wuxi, Eastern China. PARTICIPANTS Two patients, their close contacts, and relevant environments. Samples from the patients and environments were collected and tested by real time reverse transcriptase-polymerase chain reaction (rRT-PCR), viral culture, and haemagglutination inhibition assay. Any contacts who became ill had samples tested for avian H7N9 by rRT-PCR. Paired serum samples were obtained from contacts for serological testing by haemagglutination inhibition assays. MAIN OUTCOMES MEASURES Clinical data, history of exposure before the onset of illnesses, and results of laboratory testing of pathogens and further analysis of sequences and phylogenetic tree to isolated strains. RESULTS The index patient became ill five to six days after his last exposure to poultry. The second patient, his daughter aged 32, who provided unprotected bedside care in the hospital, had no known exposure to poultry. She developed symptoms six days after her last contact with her father. Two strains were isolated successfully from the two patients. Genome sequence and analyses of phylogenetic trees showed that both viruses were almost genetically identical. Forty three close contacts of both patients were identified. One had mild illness but had negative results for avian H7N9 by rRT-PCR. All 43 close contacts tested negative for haemagglutination inhibition antibodies specific for avian H7N9. CONCLUSIONS The infection of the daughter probably resulted from contact with her father (the index patient) during unprotected exposure, suggesting that in this cluster the virus was able to transmit from person to person. The transmissibility was limited and non-sustainable.
Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV). Mother-to-child transmission of HCV occurs in 3-5% of pregnancies and accounts for most new childhood infections. HCV-specific CD8(+) cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections, but in the 60-80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition. Increased HCV replication during pregnancy suggests that maternofetal immune tolerance mechanisms may further impair HCV-specific CTLs, limiting their selective pressure on persistent viruses. To assess this possibility, we characterized circulating viral quasispecies during and after consecutive pregnancies in two women. This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that was associated with emergence of more fit viruses. CTL selective pressure was reimposed after childbirth, at which point escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply. Importantly, the viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations. Our findings indicate that the immunoregulatory changes of pregnancy reduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness.
In order to investigate the prevalence of infections with three feline retroviruses feline immunodeficiency virus (FIV), feline leukemia virus (FeLV) and feline syncytial virus (FSV) in Taiwan, we collected a total of 75 blood samples from cats from veterinary hospitals, a breeding cattery and a homeless shelter in 1993 and 1994. We examined the presences of anti-FIV and FSV antibodies and FeLV-p27 antigen in these samples by the indirect immunofluorescence and/or enzyme-linked immunosorbent assays. All of the serum samples positive for FIV were obtained from homeless cats and the overall FIV positive rate was 4%. The overall positive rates of FSV and FeLV were 28% and 1.3%, respectively. From these results, together with previous seroepidemiological surveys by others, it was revealed that the prevalence of FIV and FeLV infections appeared to be lower in Taiwan than in the United States or Japan. In contrast, the prevalence of FSV infection in Taiwan was as high as that in Japan.
Despite widespread use of antiretroviral therapies to control replication of the human immunodeficiency virus (HIV), dysfunctions of cognition that are collectively termed HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of those infected by the virus. Currently there is not a biomarker that can identify HIV-infected people who are at risk for the development of HAND. Previous studies have identified particular sphingolipid species that are dysregulated in HAND, but the neurocognitive correlates of these biochemical findings are not currently understood. To address this question, we compared cerebrospinal fluid (CSF) levels of sphingomyelin, ceramide, and sterol species with performance on standard neurological tests designed to assess the function of multiple cognitive and motor domains in HIV-infected subjects. We found that sphingomyelin:ceramide ratios for acyl chain lengths of C16∶0, C18∶0, C22∶0, and C24∶0 were associated with worse performance on several indices of memory. The most striking finding was for the acyl chain of C18∶0 that consistently associatedwith performance onmultiple tests of memory. These findings suggest that the sphingomyelin:ceramide ratio for C18∶0 may be a reasonable surrogate marker for memory dysfunction in HIV-infected subjects.
Apart from HIV two exogenous retroviruses (human T cell leukaemia viruses type I (HTLV-I) and type II (HTLV-II)) infect humans. HTLV-I infection is endemic in Japan, the Caribbean, Africa, and Melanesia and is found among immigrants from these regions in Europe. HTLV-I infection is associated with a 1-5% lifetime risk of adult T cell leukaemia/lymphoma, 1 a 0.25% lifetime risk of HTLV-I associated myelopathy, 2 and other inflammatory conditions (uveitis, alveolitis, and arthritis).1 HTLV-II infection is endemic in some native American and African peoples and among injecting drug users and has been associated with neurological disease.1 Between 1986 and 1992, 100 cases of HTLV-I associated myelopathy and 44 cases of adult T cell leukaemia/lymphoma were diagnosed in the United Kingdom.3 Adult T cell leukaemia/lymphoma was first described in 1977 and patients with it have a mean life expectancy of only six months, so most of the 44 cases were probably incident cases. …
Topical preexposure prophylaxis interrupts HIV transmission at the site of mucosal exposure. Intermittently dosed vaginal gels containing the HIV-1 reverse transcriptase inhibitor tenofovir protected pigtailed macaques depending on the timing of viral challenge relative to gel application. However, modest or no protection was observed in clinical trials. Intravaginal rings (IVRs) may improve efficacy by providing long-term sustained drug delivery leading to constant mucosal antiretroviral concentrations and enhancing adherence. Although a few IVRs have entered the clinical pipeline, 100% efficacy in a repeated macaque vaginal challenge model has not been achieved. Here we describe a reservoir IVR technology that delivers the tenofovir prodrug tenofovir disoproxil fumarate (TDF) continuously over 28 d. With four monthly ring changes in this repeated challenge model, TDF IVRs generated reproducible and protective drug levels. All TDF IVR-treated macaques (n = 6) remained seronegative and simian-HIV RNA negative after 16 weekly vaginal exposures to 50 tissue culture infectious dose SHIV162p3. In contrast, 11/12 control macaques became infected, with a median of four exposures assuming an eclipse of 7 d from infection to virus RNA detection. Protection was associated with tenofovir levels in vaginal fluid [mean 1.8 × 10(5) ng/mL (range 1.1 × 10(4) to 6.6 × 10(5) ng/mL)] and ex vivo antiviral activity of cervicovaginal lavage samples. These observations support further advancement of TDF IVRs as well as the concept that extended duration drug delivery devices delivering topical antiretrovirals could be effective tools in preventing the sexual transmission of HIV in humans.
Human cytomegalovirus (HCMV) is one of the largest known DNA viruses. It is ubiquitous, and following resolution of primary productive infection, it persists in the human host by establishing a lifelong latent infection in myeloid lineage cells such as monocytes and their progenitors. Most adults with HCMV infection are healthy but it can cause neurologic deficits in infants, and remains an important cause of morbidity and mortality in the immunosuppressed patient. Microarray-based studies of HCMV have provided useful information about genes that are transcriptionally active during both productive and latent phases of infection. This chapter describes how to study genes in HCMV using microarrays and two cell types (productively infected human foreskin fibroblasts, and latently infected primary human myeloid progenitor cells).
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes life-threatening disease in patients who are immunosuppressed for bone marrow or tissue transplantation or who have AIDS (ref. 1). HCMV establishes lifelong latent infections and, after periodic reactivation from latency, uses a panel of immune evasion proteins to survive and replicate in the face of robust, fully primed host immunity. Monocyte/macrophages are important host cells for HCMV, serving as a latent reservoir and as a means of dissemination throughout the body. Macrophages and other HCMV-permissive cells, such as endothelial and glial cells, can express MHC class II proteins and present antigens to CD4+ T lymphocytes. Here, we show that the HCMV protein US2 causes degradation of two essential proteins in the MHC class II antigen presentation pathway: HLA-DR-α and DM-α. This was unexpected, as US2 has been shown to cause degradation of MHC class I (refs. 5,6), which has only limited homology with class II proteins. Expression of US2 in cells reduced or abolished their ability to present antigen to CD4+ T lymphocytes. Thus, US2 may allow HCMV-infected macrophages to remain relatively 'invisible' to CD4+ T cells, a property that would be important after virus reactivation.
Background. Hepatitis C virus (HCV) is an underappreciated cause of pediatric liver disease, most frequently acquired by vertical transmission (VT). Current guidelines that include the option of screening infants for HCV RNA at 1-2 months are based on data prior to current real-time polymerase chain reaction (PCR)-based testing. Previous studies have demonstrated VT rates of 4%-15% and an association with high maternal viral load. We evaluated HCV RNA in infants with HCV VT and assessed maternal risk factors in a prospective cohort in Cairo, Egypt. Methods. Pregnant women were screened for HCV from December 2012 to March 2014. For those with HCV viremia, their infants were tested at 12 months for HCV RNA using real-time PCR. Maternal risk factors assessed for HCV VT association included HCV RNA levels, mode of delivery, and maternal IL28B genotype. Results. Of 2514 women screened, a total of 54 women were viremic (2.1%) and delivered 56 infants. Of those, 51 infants of 49 women were tested at 12 months of age. Only 7 infants were viremic, with an HCV VT rate of 14.3% (7 of 49). Median HCV RNA in the infants was 2100 IU/mL. None of the maternal risk factors analyzed were associated with transmission. Conclusions. In Egypt where HCV is highly endemic, we observed an overall 12-month HCV VT rate of 14.3%. Further studies should focus on better identification of pregnant women more likely to vertically transmit HCV and earlier testing of infants to identify those likely to develop chronicity.
HIV causes a chronic infection characterized by depletion of CD4(+) T lymphocytes and the development of opportunistic infections. Despite drugs that inhibit viral spread, HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy (HAART) and the immune response. Here we used CD34(+) cells from infected people as well as in vitro studies of wild-type HIV to show infection and killing of CD34(+) multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection.
OBJECTIVE Rates of hepatitis C (HCV) infection, testing, and treatment were compared among patients with schizophrenia, a substance use disorder, or co-occurring schizophrenia or schizoaffective disorder and a substance use disorder and a control group. METHODS Information about 293,445 patients of the Northwest Veterans Healthcare Administration was obtained. RESULTS The substance use disorder group constituted 13.6 percent of the sample; the schizophrenia group, 1.6 percent; and the co-occurring-disorders group, 1.4 percent. Respectively, these groups were approximately four, two, and six times as likely as the control group to receive HCV testing and about seven, two, and eight times as likely to be infected. The rate of interferon (IFN) therapy was significantly lower for the substance use group and the group with co-occurring disorders. However, the magnitude of the differences was not substantial, suggesting that these high-risk groups were not excluded from IFN therapy.
Human and simian immunodeficiency virus (HIV and SIV) replicate optimally in activated memory CD4(+) T cells, a cell type that is abundant in the intestine. SIV infection of rhesus monkeys resulted in profound and selective depletion of CD4+ T cells in the intestine within days of infection, before any such changes in peripheral lymphoid tissues. The loss of CD4+ T cells in the intestine occurred coincident with productive infection of large numbers of mononuclear cells at this site. The intestine appears to be a major target for SIV replication and the major site of CD4+ T cell loss in early SIV infection.
Kaposi's sarcoma-associated herpesvirus (KSHV), also termed human herpesvirus type 8, is consistently identified in Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. Here we report four cases of KSHV-bearing solid lymphomas that occurred in AIDS patients (cases 1 to 3) and in a human immunodeficiency virus (HIV)-seronegative person (case 4). The patients presented extranodal masses in the abdomen (cases 1, 3, and 4) or skin (case 2), and nodal involvement, together with Kaposi's sarcoma (case 3). The gastrointestinal tract was involved in two patients (cases 1 and 3). The patients did not develop a lymphomatous effusion. KSHV was detected in the tumor cells of all cases by immunohistochemistry and by polymerase chain reaction. Epstein-Barr virus was detected in two of the HIV-related cases. All KSHV-positive solid lymphomas exhibited PEL-like cell morphology. To investigate the relationship of these disorders to PEL and to other AIDS-associated diffuse large cell lymphomas, KSHV-positive solid lymphomas were tested for the expression of a set of genes that were previously shown by gene profiling analysis to define PEL tumor cells. The results showed that expression of this set of genes in KSHV-positive lymphomas is similar to that of PEL but distinct from KSHV-negative AIDS-associated diffuse large cell lymphomas. Because pathobiological features of KSHV-positive solid lymphomas closely mimic those of PEL, our results suggest that KSHV-positive solid lymphomas should be considered as a tissue-based variant of classical PEL, irrespective of HIV status.
Background. Artemisinin-based combination therapy (ACT) reduces microscopically confirmed gametocytemia and mosquito infection. However, molecular techniques have recently revealed high prevalences of submicroscopic gametocytemia. Our objective here was to determine the effect of sulfadoxine-pyrimethamine (SP) monotherapy and treatment with SP plus amodiaquine (AQ), SP plus artesunate (AS), and artemether-lumefantrine (AL; Coartem) on submicroscopic gametocytemia and infectiousness. Methods. Kenyan children (n=528) 6 months-10 years of age were randomized to 4 treatment arms. Gametocytemia was determined by both microscopy and Pfs25 RNA-based quantitative nucleic acid sequence-based amplification (Pfs25 QT-NASBA). Transmission was determined by membrane-feeding assays. Results. Gametocyte prevalence, as determined by Pfs25 QT-NASBA, was 89.4% (219/245) at enrollment and decreased after treatment with SP plus AS, SP plus AQ, and AL. Membrane-feeding assays for a group of randomly selected children revealed that the proportion of infectious children was as much as 4-fold higher than expected when based on microscopy. ACT did not significantly reduce the proportion of infectious children but did reduce the proportion of infected mosquitoes. Conclusions. Submicroscopic gametocytemia is common after treatment and contributes considerably to mosquito infection. Our findings should be interpreted in the context of transmission intensity, but the effect of ACT on malaria transmission appears to be moderate and restricted to the duration of gametocyte carriage and the proportion of mosquitoes that are infected by carriers.
BACKGROUND In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. METHODS AND FINDINGS We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. CONCLUSIONS This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.