Deborah Persaud

Neurocysticercosis in an Orthodox Jewish community in New York City.

BACKGROUND AND METHODS From June 1990 through July 1991, intracerebral infection with the larval stage of the pork tapeworm Taenia solium was diagnosed in four unrelated persons in an Orthodox Jewish community in New York City. None of the patients had eaten pork, and only one had traveled to a country in which T. solium infection was endemic. We investigated this outbreak, screened serum samples from family members and household contacts for antibodies to cysticercosis, and examined stool specimens from household employees for eggs of taenia species. RESULTS The four patients had recurrent seizures and brain lesions that were radiologically consistent with the presence of cysticerci. The diagnosis was confirmed in two patients by a brain biopsy, and in two by immunoblot assays for cysticercus antibodies. Of 17 immediate family members screened serologically, 7 from two families had cysticercus antibodies. Magnetic resonance imaging of the brain showed cystic lesions in two of the seropositive family members, one of whom had had a seizure. Examinations of six domestic employees from all four households revealed an active infection with taenia species in one and a positive serologic test in another. Since these women had recently emigrated from Latin American countries where T. solium infection is endemic, they were the most likely sources of infection in the members of these households. CONCLUSIONS A diagnosis of neurocysticercosis should be considered in patients with seizures and radiologic evidence of cystic brain lesions, even in those who do not eat pork and who have not traveled to a country in which T. solium infection is endemic. Recent emigrants from countries in which T. solium infection is endemic should be screened for tapeworm infection in their stools before they are employed as housekeepers or food handlers.

Residual Human Immunodeficiency Virus Type 1 Viremia in Some Patients on Antiretroviral Therapy Is Dominated by a Small Number of Invariant Clones Rarely Found in Circulating CD4+ T Cells

ABSTRACT Antiretroviral therapy can reduce human immunodeficiency virus type 1 (HIV-1) viremia to below the detection limit of ultrasensitive clinical assays (50 copies of HIV-1 RNA/ml). However, latent HIV-1 persists in resting CD4+ T cells, and low residual levels of free virus are found in the plasma. Limited characterization of this residual viremia has been done because of the low number of virions per sample. Using intensive sampling, we analyzed residual viremia and compared these viruses to latent proviruses in resting CD4+ T cells in peripheral blood. For each patient, we found some viruses in the plasma that were identical to viruses in resting CD4+ T cells by pol gene sequencing. However, in a majority of patients, the most common viruses in the plasma were rarely found in resting CD4+ T cells even when the resting cell compartment was analyzed with assays that detect replication-competent viruses. Despite the large diversity of pol sequences in resting CD4+ T cells, the residual viremia was dominated by a homogeneous population of viruses with identical pol sequences. In the most extensively studied case, a predominant plasma sequence was also found in analysis of the env gene, and linkage by long-distance reverse transcriptase PCR established that these predominant plasma sequences represented a single predominant plasma virus clone. The predominant plasma clones were released for months to years without evident sequence change. Thus, in some patients on antiretroviral therapy, the major mechanism for residual viremia involves prolonged production of a small number of viral clones without evident evolution, possibly by cells other than circulating CD4+ T cells.

Absence of Detectable HIV-1 Viremia after Treatment Cessation in an Infant

An infant born to a woman with human immunodeficiency virus type 1 (HIV-1) infection began receiving antiretroviral therapy (ART) 30 hours after birth owing to high-risk exposure. ART was continued when detection of HIV-1 DNA and RNA on repeat testing met the standard diagnostic criteria for infection. After therapy was discontinued (when the child was 18 months of age), levels of plasma HIV-1 RNA, proviral DNA in peripheral-blood mononuclear cells, and HIV-1 antibodies, as assessed by means of clinical assays, remained undetectable in the child through 30 months of age. This case suggests that very early ART in infants may alter the establishment and long-term persistence of HIV-1 infection.

Effectiveness of antiretroviral therapy among HIV-infected children in sub-Saharan Africa

Assessment of antiretroviral treatment programmes for HIV-infected children in sub-Saharan Africa is important to enable the development of effective care and improve treatment outcomes. We review the effectiveness of paediatric antiretroviral treatment programmes in sub-Saharan Africa and discuss the implications of these findings for the care and treatment of HIV-infected children in this region. Available reports indicate that programmes in sub-Saharan Africa achieve treatment outcomes similar to those in North America and Europe. However, progress in several areas is required to improve the care of HIV-infected children in sub-Saharan Africa. The findings emphasise the need for low-cost diagnostic tests that allow for earlier identification of HIV infection in infants living in sub-Saharan Africa, improved access to antiretroviral treatment programmes, including expansion of care into rural areas, and the integration of antiretroviral treatment programmes with other health-care services, such as nutritional support.

Genotypic Analysis of HIV-1 Drug Resistance at the Limit of Detection: Virus Production without Evolution in Treated Adults with Undetectable HIV Loads

Human immunodeficiency virus (HIV) production continues in patients receiving highly active antiretroviral therapy (HAART) with undetectable (<50 copies/mL) virus loads. Our initial cross-sectional study showed that this viremia is composed of viruses that lack new resistance mutations to the HAART regimen. Here we describe a longitudinal, clonal genotypic analysis of plasma virus loads in treated adults who had undetectable virus loads. We document a continuous production of virus in 8 HIV-1-infected adults who maintained suppression of viremia for up to 15 months. Using analytical approaches for distinguishing selected resistance mutations from nonselected mutations and polymerase chain reaction errors, we detected no evolution of resistance in the reverse-transcriptase and protease genes. Sporadic resistance mutations were detected in some viral clones that were not selected for subsequently. Thus, in some patients, HAART suppresses replication to a level that does not allow the evolution of drug resistance over a time frame of years.

Latency in Human Immunodeficiency Virus Type 1 Infection: No Easy Answers

In summary, HIV-1 latency represents a formidable therapeutic challenge for which there are no easy answers. As a result of viral tropism for activated CD4+ T cells and the reversion of some of these cells to a profoundly quiescent and long-lived memory state, the virus can persist through the same mechanisms responsible for the most fundamental characteristic of the immune system, immunologic memory. The dependence of viral gene expression on host factors that are inactive in resting T cells means that viral gene expression can be largely or completely extinguished in latently infected cells. In the absence of virus gene expression, latently infected cells will differ from their uninfected counterparts by only the presence of 10 kb of viral DNA integrated into a host cell chromosome. In this case, the virus is persisting as genetic information in a stably integrated form in rare memory cells that cannot be distinguished from their uninfected counterparts. It is difficult to envision any targeting mechanism that will allow specific elimination of this reservoir. Optimism stems from the fact that antiretroviral drugs come very close to stopping the active replication of the virus, with its attendant damage to the immune system. In some patients on HAART, the evolution of drug-resistant viruses, which is the principal cause of treatment failure, is largely halted. The development of nontoxic, convenient, and affordable combinations of antiretroviral drugs may allow infected individuals to live a normal life despite the indefinite persistence of latent HIV-1 in resting memory CD4+ T cells.

A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children

HIV-1 persists in a latent state in resting CD4(+) T lymphocytes of infected adults despite prolonged highly active antiretroviral therapy (HAART). To determine whether a latent reservoir for HIV-1 exists in infected children, we performed a quantitative viral culture assay on highly purified resting CD4(+) T cells from 21 children with perinatally acquired infection. Replication-competent HIV-1 was recovered from all 18 children from whom sufficient cells were obtained. The frequency of latently infected resting CD4(+) T cells directly correlated with plasma virus levels, suggesting that in children with ongoing viral replication, most latently infected cells are in the labile preintegration state of latency. However, in each of 7 children who had suppression of viral replication to undetectable levels for 1-3 years on HAART, latent replication-competent HIV-1 persisted with little decay, owing to a stable reservoir of infected cells in the postintegration stage of latency. Drug-resistance mutations generated by previous nonsuppressive regimens persisted in this compartment despite more than 1 year of fully suppressive HAART, rendering untenable the idea of recycling drugs that were part of failed regimens. Thus the latent reservoir for HIV-1 in resting CD4(+) T cells will be a major obstacle to HIV-1 eradication in children.

Novel Single-Cell-Level Phenotypic Assay for Residual Drug Susceptibility and Reduced Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected individuals who develop drug-resistant virus during antiretroviral therapy may derive benefit from continued treatment for two reasons. First, drug-resistant viruses can retain partial susceptibility to the drug combination. Second, therapy selects for drug-resistant viruses that may have reduced replication capacities relative to archived, drug-sensitive viruses. We developed a novel single-cell-level phenotypic assay that allows these two effects to be distinguished and compared quantitatively. Patient-derived gag-pol sequences were cloned into an HIV-1 reporter virus that expresses an endoplasmic reticulum-retained Env-green fluorescent protein fusion. Flow cytometric analysis of single-round infections allowed a quantitative analysis of viral replication over a 4-log dynamic range. The assay faithfully reproduced known in vivo drug interactions occurring at the level of target cells. Simultaneous analysis of single-round infections by wild-type and resistant viruses in the presence and absence of the relevant drug combination divided the benefit of continued nonsuppressive treatment into two additive components, residual virus susceptibility to the drug combination and selection for drug-resistant variants with diminished replication capacities. In some patients with drug resistance, the dominant circulating viruses retained significant susceptibility to the combination. However, in other cases, the dominant drug-resistant viruses showed no residual susceptibility to the combination but had a reduced replication capacity relative to the wild-type virus. In this case, simplification of the regimen might still allow adequate suppression of the wild-type virus. In a third pattern, the resistant viruses had no residual susceptibility to the relevant drug regimen but nevertheless had a replication capacity equivalent to that of wild-type virus. In such cases, there is no benefit to continued treatment. Thus, the ability to simultaneously analyze residual susceptibility and reduced replication capacity of drug-resistant viruses may provide a basis for rational therapeutic decisions in the setting of treatment failure.

Persistence of Wild-Type Virus and Lack of Temporal Structure in the Latent Reservoir for Human Immunodeficiency Virus Type 1 in Pediatric Patients with Extensive Antiretroviral Exposure

ABSTRACT Although highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection can reduce levels of HIV-1 RNA in plasma to below the limit of detection, replication-competent forms of the virus persist in all infected individuals. One form of persistence involves a stable reservoir of latent but potentially infectious virus that resides in resting memory CD4+ T cells. The mechanisms involved in maintaining this latent reservoir are incompletely understood. In the present study, we examined the dynamic characteristics of this reservoir in a cohort of children who developed drug-resistant HIV-1 as a result of extensive exposure to inadequately suppressive one- or two-drug regimens prior to the advent of HAART. We have previously shown that drug-resistant viruses selected by nonsuppressive pre-HAART regimens can enter and persist in this reservoir. We have extended these findings here by demonstrating that archival wild-type HIV-1 persists in this reservoir despite the fact that in these patients drug-resistant mutants have been favored by the selective conditions for many years. Phylogenetic analysis of replication-competent viruses persisting in resting CD4+ T cells revealed a striking lack of temporal structure in the sense that isolates obtained at later time points did not show greater sequence divergence than isolates from earlier time points. The persistence of drug-sensitive virus and the lack of temporal structure in the latent reservoir provide genetic evidence for the idea that HIV-1 can persist in a latent form free of selective pressure from antiretroviral drugs in long-lived resting memory CD4+ T cells. Although there may be other mechanisms for viral persistence, this stable pool of latently infected cells is of significant concern because of its potential to serve as a lasting source of replication-competent viruses, including the infecting wild-type form and all drug-resistant variants that have arisen subsequently.

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the groups strategy.