Mark Zuckerman

Impact of HIV-1 viral subtype on disease progression and response to antiretroviral therapy

BackgroundOur intention was to compare the rate of immunological progression prior to antiretroviral therapy (ART) and the virological response to ART in patients infected with subtype B and four non-B HIV-1 subtypes (A, C, D and the circulating recombinant form, CRF02-AG) in an ethnically diverse population of HIV-1-infected patients in south London.MethodsA random sample of 861 HIV-1-infected patients attending HIV clinics at Kings and St Thomas hospitals were subtyped using an in-house enzyme-linked immunoassay and env sequencing. Subtypes were compared on the rate of CD4 cell decline using a multi-level random effects model. Virological response to ART was compared using the time to virological suppression (< 400 copies/ml) and rate of virological rebound (> 400 copies/ml) following initial suppression.ResultsComplete subtype and epidemiological data were available for 679 patients, of whom 357 (52.6%) were white and 230 (33.9%) were black African. Subtype B (n = 394) accounted for the majority of infections, followed by subtypes C (n = 125), A (n = 84), D (n = 51) and CRF02-AG (n = 25). There were no significant differences in rate of CD4 cell decline, initial response to highly active antiretroviral therapy and subsequent rate of virological rebound for subtypes B, A, C and CRF02-AG. However, a statistically significant four-fold faster rate of CD4 decline (after adjustment for gender, ethnicity and baseline CD4 count) was observed for subtype D. In addition, subtype D infections showed a higher rate of virological rebound at six months (70%) compared with subtypes B (45%, p = 0.02), A (35%, p = 0.004) and C (34%, p = 0.01)ConclusionsThis is the first study from an industrialized country to show a faster CD4 cell decline and higher rate of subsequent virological failure with subtype D infection. Further studies are needed to identify the molecular mechanisms responsible for the greater virulence of subtype D.

Hepatitis B virus infection: pathogenesis, reactivation and management in hematopoietic stem cell transplant recipients

Hepatitis B virus (HBV) is a partially double stranded DNA virus that can integrate into host cell chromosomes as covalently closed circular DNA forms. HBV reactivation following hematopoietic stem cell transplantation in recipients with evidence of past HBV exposure, as well as exacerbation of a current HBV infection in HBV carrier recipients, secondary to chemotherapy and post-transplant immunosuppression that affect both humoral and cell-mediated control of HBV infection, are well documented in the literature. Management options include HBV-DNA screening and antiviral prophylaxis. Nucleos(t)ide analogues have been used at the start of chemotherapy and pretransplantation, with the course continuing for 6 months. However, depending on the serum HBV-DNA level, the antiviral agent might be given until a therapeutic end point is reached.

Attenuation of virulence in influenza B viral infection of volunteers

A study was performed with volunteers in order to determine whether the virulence of an influenza B viral infection could be attenuated. Of a total of 62 persons, 26 received intranasal inoculations of an unpassaged influenza B virus isolate [virus U], while 26 received the same virus isolated passaged in cell culture and then in special pathogen-free embryonated hens eggs [virus P]. The remaining 10 persons received uninoculated cell culture medium. Daily nasal wash samples were collected post-infection and scores for illness in the volunteers were evaluated. Viruses were isolated in cell culture and in eggs. Isolates were analysed by means of monoclonal antibodies (MAbs) raised against the influenza B viral haemagglutinin (HA) glycoprotein. One-step and nested polymerase chain reactions as well as direct nucleotide sequence analysis of part of the HA gene of the unpassaged specimens, together with the influenza B viruses isolated from those specimens, were performed. Nine of 26 volunteers who received the unpassaged virus became ill (illness scores from 13-84/100) whereas 7/26 of the volunteers who received the passaged virus had very mild illness (illness scores from 3-7/100). All the other volunteers remained well. Results of analysing the clinical specimens collected from the two groups of volunteers were compared. A difference in MAb reactivity, together with an aspartate for asparagine amino acid substitution at position 196 in a 432 base pair region of the viral HA gene, was observed. The loss of a potential glycosylation site at amino acid position 196-198 in the viral HA was associated with attenuation of virulence. This finding may have implications for the formulation of influenza vaccines.

Global burden of herpes simplex type 2

www.thelancet.com/infection Vol 9 June 2009 333 In conclusion, considering the complications and defective functioning of the cellular immune system as a consequence of chronic coinfection of M tuberculosis and HIV, we believe that the strategy of inducing nonneutralising antibodies by therapeutic vaccination might not be appropriate for these patients. The primary goal in treating patients with coinfection should be the rejuvenation of the immune system, making it functionally fi t before implementing any vaccination strategies. However, common features of these two infectious agents, such as use of the same receptor (dendritic cell-specifi c intercellular adhesion molecule-3grabbing non-integrin) by both glycoprotein 120 of HIV and mannosylated lipoarabinomannan of M tuberculosis, complicate the dissection of pathogenesis due to individual pathogens in patients with coinfection. In addition, two important factors that govern the immune response to pathogens and vaccination have to be considered: nutrition and intestinal parasite burden. This point is crucial since most of the patients with coinfection are in developing countries and it is well known that nutrition and intestinal parasite burden can bias the type of immune response to pathogens and vaccines. Therefore, the pathogenesis of coinfection might not be the same among patients in developing and developed countries. As individuals living with coinfection of HIV and tuberculosis grow older, it will become important to consider the immune system that is aff ected by infections, nutritional status, past therapeutic history, and age. Therefore, the need of the hour in these patients will be a thorough investigation of the pathogenesis of coinfection and identifying appropriate therapeutic strategies that boost the immune system.

Unsupervised self-initiation of antiretroviral drugs in a newly diagnosed HIV-1 infected haemodialysis patient.

A 50-year-old Afro-Caribbean male with underlying hypertenion and chronic kidney disease stage 5 was found to be HIV-1 ntibody positive after annual screening for HIV in the renal unit. e had been expecting this result as his new female partner had een found to be HIV-1 infected having been admitted to hospial recently from the accident and emergency department with uberculosis. He had been on haemodialysis for the preceding years and was active on the national cadaveric kidney translant list, from which he was suspended pending control of his IV infection. His baseline HIV-1 RNA load was 92,400 copies/ml 5.0 log10) with a CD4 count of 251 cells/mm3 (19%). No antiretroiral resistance mutations were found on baseline HIV-1 drug esistance testing. The partner also had wild-type virus on baseine testing. He was booked in to the HIV clinic where he was o be started on combination antiretroviral therapy (cART) but efaulted his first clinic appointment and was seen 3 months after