Discovery of O-Linked Carbohydrate on HIV-1 Envelope and Its Role in Shielding against One Category of Broadly Neutralizing Antibodies.

Approximately 50% of the mass of the Envelope (Env) glycoprotein surface subunit (gp120) of human immunodeficiency virus type 1 (HIV-1) is composed of N-linked carbohydrate. Until now, the dogma has been that HIV-1 lacks O-linked carbohydrate on Env. Here we show that a subset of patient-derived HIV-1 isolates contain O-linked carbohydrate on the variable 1 (V1) domain of Env gp120. We demonstrate the presence of this O-glycosylation both on virions and on gp120 expressed as a secreted protein. Further, we establish that these O-linked glycans can confer a more than 1,000-fold decrease in neutralization sensitivity (IC50) to V3-glycan broadly neutralizing antibodies. These findings uncover a structural modification to the HIV-1 Env and suggest a functional role in promoting viral escape from one category of broadly neutralizing antibodies.

A Highly Unusual V1 Region of Env in an Elite Controller of HIV Infection.

HIV elite controllers represent a remarkable minority of patients who maintain normal CD4+ T-cell counts and low or undetectable viral loads for decades in the absence of antiretroviral therapy. To examine the possible contribution of virus attenuation to elite control, we obtained a primary HIV-1 isolate from an elite controller who had been infected for 19 years, the last 10 of which were in the absence of antiretroviral therapy. Full-length sequencing of this isolate revealed a highly unusual V1 domain in Envelope (Env). The V1 domain in this HIV-1 strain was 49 amino acids, placing it in the top 1% of lengths among the 6,112 Env sequences in the Los Alamos National Laboratory online database. Furthermore, it included two additional N-glycosylation sites and a pair of cysteines suggestive of an extra disulfide loop. Virus with this Env retained good infectivity and replicative capacity; however, analysis of recombinant viruses suggested that other sequences in Env were adapted to accommodate the unusual V1 domain. While the long V1 domain did not confer resistance to neutralization by monoclonal antibodies of the V1/V2-glycan-dependent class, it did confer resistance to neutralization by monoclonal antibodies of the V3-glycan-dependent class. Our findings support results in the literature that suggest a role for long V1 regions in shielding HIV-1 from recognition by V3-directed broadly neutralizing antibodies. In the case of the elite controller described here, it seems likely that selective pressures from the humoral immune system were responsible for driving the highly unusual polymorphisms present in this HIV-1 Envelope.IMPORTANCE Elite controllers have long provided an avenue for researchers to reveal mechanisms underlying control of HIV-1. While the role of host genetic factors in facilitating elite control is well known, the possibility of infection by attenuated strains of HIV-1 has been much less studied. Here we describe an unusual viral feature found in an elite controller of HIV-1 infection and demonstrate its role in conferring escape from monoclonal antibodies of the V3-glycan class. Our results suggest that extreme variation may be needed by HIV-1 to escape neutralization by some antibody specificities.

The early use of Pasteur's rabies vaccine in the United States.

Louis Pasteur's vaccine against rabies was introduced in France during 1885. A year later it became available within the United States. This article tells the story of the first use of the Pasteur vaccine in America and describes the early history of the vaccine's production and distribution across the country by Pasteur Institutes established for this purpose. Highlights of Pasteur's landmark studies on rabies are presented: research which pioneered the field of virology and the use of immunization to prevent infectious diseases.

Description of a pilot anal pap smear screening program among individuals attending a Veteran's Affairs HIV clinic.

Despite the higher risk of anal cancer among HIV-infected individuals currently there are no national or international guidelines for anal dysplasia screening. We assessed acceptance and feasibility of screening for anal intraepithelial neoplasia (AIN), the rate of abnormalities, and relationship between the presence of AIN and a history of receptive anal intercourse. Eighty-two percent of HIV-patients approached during routine clinic visit agreed to participate in the study with anal Pap smear collection; 53% had abnormal cytology results and among those undergoing high-resolution anoscopy with biopsy, 55% had high-grade AIN, including 2 cases of carcinoma in situ. Anal cytology was well accepted and it was feasible to be incorporated into HIV primary care practice. Abnormal cytology was not significantly associated with history of anal intercourse (p = 0.767). The high rate of abnormal results reinforces the need for further evaluation of the role of systematic anal Pap smear screening for HIV patients.

Rare infections are just an airplane trip away: Salmonella typhi meningitis in a recent immigrant to the United States.

We report a case of a 24-year-old immigrant from Bangladesh with Salmonella typhi meningitis, a rare disease in the United States, especially among adults. The common manifestations of meningitis such as neck rigidity and changes in mental status did not develop and Kernig sign was absent. The patient was successfully treated with intravenous ceftriaxone. This case demonstrates the importance of considering endemic infections in the country of origin when recent immigrants and returnees to the United States present with febrile illness.

Differences in presentation and outcome of invasive pneumococcal disease among patients with and without HIV infection in the pre-HAART era.

Invasive pneumococcal disease (PD) occurs frequently among HIV-infected patients, but it is unclear whether its manifestations and outcome are different compared to those observed among patients without HIV-1 infection. Because the immune reconstitution that accompanies antiretroviral therapy may change some of these features and because most cases of HIV- 1 infection occur in resource-poor settings of the world where access to antiretroviral agents is limited, we compared PD among patients with and without HIV-1 infection in a North American population before the introduction of highly active antiretroviral therapy (HAART). The records of all pneumococcal cultures processed at this medical center over a period of 20 months were used to identify patients with invasive PD. Hospital records were reviewed for 103 of these patients (52 with and 51 without HIV-1 infection) and demographic, clinical, laboratory, radiographic, and microbiologic information was abstracted and subsequently analyzed. Despite similarities in presenting signs and symptoms, we found a higher incidence of bacteremia but a more favorable outcome with less frequent requirements for intubation and admission to intensive care units and better survival among individuals with HIV infection. Factors such as less advanced age, the presence of fewer comorbid conditions, or a less florid inflammatory response among HIV-infected individuals may account for differences in outcome of invasive PD.

Development of anti-retroviral resistance of HIV-1 infected individuals on therapy: is it inevitable?

Highly active antiretroviral therapy directed against HIV-1 has dramatically modified morbidity and mortality in infected individuals. Enthusiasm for the success of these medications have been tempered by an inability to clear virus from the infected host leaving a virus poised to leverage any advantage into one of productive survival. One mechanism used to accomplish escape from suppression secondary to antiretroviral therapy is by developing mutations. The goal of therapy has been to diminish viral replication, thereby effectively abrogating the development of these resistance-bearing mutations. This strategy has met with significant success but numerous host-viral factors impact on the ability of the clinician to persistently suppress viral load, thereby providing a window of opportunity for the virus to mutate. In particular we review evidence for ongoing viral replication in the face of suppressive antiretroviral therapy and viral replication in tissue compartments. We discuss whether viral resistance can develop during transient elevations in viral load (viral blips) or as a function of the rate of viral load decay while on therapy. Finally, we touch on the therapeutic strategy that diminished viral replication capacity of mutational species can maintain host immunity.

Genotypic analysis of plasma HIV-1 RNA after influenza vaccination of patients with previously undetectable viral loads.

OBJECTIVE: In this study we evaluated the possibility that plasma viral load elevations secondary to influenza vaccination in HIV-1-seropositive individuals with previously undetectable viral loads (< 200 copies/ml) could develop resistance-bearing mutations in the viral reverse transcriptase (RT) and protease regions. METHODS: Thirty-four patients with undetectable viral burdens on highly active antiretroviral therapy (HAART) were evaluated for elevations in plasma viral load 2 and 4 weeks post-influenza vaccination. Plasma from patients whose viral load increased after vaccination was subject to genotypic resistance analysis by the line probe assay (LiPA) to determine whether primary resistance-bearing mutations developed during this period and at follow-up. Stored plasma was used to evaluate whether RT or protease mutations existed pre-vaccination. RESULTS: Seven out of 34 patients were found to experience elevations in their viral load after influenza vaccination. Two of the patients revealed evidence of primary RT or protease mutations not demonstrated in earlier pre-vaccination samples. One patient failed therapy after vaccination, and one patient revealed post-vaccination viral load elevations that eventually led to the progressive development of primary zidovudine mutations. CONCLUSION: Evidence is presented that supports the contention that a small subset of patients who experience viral load elevations after influenza vaccination can develop mutational changes in the RT region of the viral genome either acutely or after a failure of the viral load to return to undetectable levels.

Pulmonary Nocardiosis.

Pulmonary nocardiosis is an uncommon but serious infection that is increasingly found in immunosuppressed persons, especially transplant recipients and persons with AIDS. The Nocardia species are denizens of soil and decaying plants that gain entry to humans through inhalation or inoculation. Pulmonary nocardiosis typically presents as an acute to subacute necrotizing pneumonia, with a variable clinical picture. Metastatic infections of the brain and subcutaneous tissues are common complications. Most clinical laboratories can isolate these microorganisms, but final speciation may be a challenge and antimicrobial susceptibility testing is especially difficult because of the slow rate of growth of Nocardia species. Full identification of species and susceptibility testing is important because of the epidemiologic implications and the difficulties of successfully treating these infections in immunosuppressed patients. Sulfonamides, including trimethoprim-sulfamethoxazole, remain the most reliable antimicrobials. Many alternative agents are active against Nocardia in vitro, but clinical data are limited.