Sexually transmitted infections (STI) in men who have sex with men (MSM)

The impact of increasingly efficient antiretroviral therapy (ART) on survival and general well-being has contributed to a "business as usual" attitude to sex among men who have sex with men (MSM). There has been a recent marked increase of sexually transmitted infections (STI) including syphilis, LGV and Hepatits C among MSM. STIs located in the oral cavity or rectum are asymptomatic in over 80% and 50%, respectively and these sites must be seen as important reservoirs. On the other hand severe proctitis may be mistreated as inflammatory bowel disease without adequate medical history and testing. Due to the reappearance of syphilis, all genital ulcers, non-itching exanthema and severe disease symptoms (e.g. fever, fatigue, lymphadenopathy, hepato-splenomegaly, increased liver enzymes, neurological and ophthalmologic symptoms without other explanations) should lead to testing for syphilis. There is a marked association between STIs and HIV. Syphilis, LGV and Hepatits C are strongly overrepresented in HIV positive MSM, while gonorrhoea, LGV and syphilis increase the HIV susceptibility. Syphilis leads to increased viral load in HIV positive. The major risk factors for Hepatitis B are number of sex partners and receptive anal intercourse. High grade Human Papilloma Virus (HPV) anal lesions can progress to cancer. There is a 30 fold increase risk for anal cancer among MSM, a risk that is doubled in HIV infection, making anal cancer one of the most common non-AIDS tumors. All MSM should be offered Hepatitis A and B vaccination and the inclusion of boys in HPV vaccination programs must be considered. The aim of this article is to describe asymptomatic and symptomatic bacterial and viral STIs of the oral cavity, penis/urethra and rectum and the sexually transmittable viral Hepatitis and HIV in MSM and to inspire the medical establishment to adhere to testing guidelines in this group. This article is built on a review of published findings, the presentation of own data on Gonorrhoea and chlamydia and our own experience in treating all STIs including HIV in MSM since 1982 at a Gay Men's Health Clinic (Venhälsan) at Stockholm South General Hospital, Sweden

HIV-DNA Given with or without Intradermal Electroporation Is Safe and Highly Immunogenic in Healthy Swedish HIV-1 DNA/MVA Vaccinees: A Phase I Randomized Trial

We compared safety and immunogenicity of intradermal (ID) vaccination with and without electroporation (EP) in a phase I randomized placebo-controlled trial of an HIV-DNA prime HIV-MVA boost vaccine in healthy Swedish volunteers.HIV-DNA plasmids encoding HIV-1 genes gp160 subtypes A, B and C; Rev B; Gag A and B and RTmut B were given ID at weeks 0, 6 and 12 in a dose of 0.6 mg. Twenty-five volunteers received vaccine using a needle-free device (ZetaJet) with (n=16) or without (n=9) ID EP (Dermavax). Five volunteers were placebo recipients. Boosting with recombinant MVA-CMDR expressing HIV-1 Env, Gag, Pol of CRF01_AE (HIV-MVA) or placebo was performed at weeks 24 and 40. Nine of the vaccinees received a subtype C CN54 gp140 protein boost together with HIV-MVA.The ID/EP delivery was very well tolerated. After three HIV-DNA immunizations, no statistically significant difference was seen in the IFN-γ ELISpot response rate to Gag between HIV-DNA ID/EP recipients (5/15, 33%) and HIV-DNA ID recipients (1/7, 14%, p=0.6158). The first HIV-MVA or HIV-MVA+gp140 vaccination increased the IFN-γ ELISpot response rate to 18/19 (95%). CD4+ and/or CD8+ T cell responses to Gag or Env were demonstrable in 94% of vaccinees. A balanced CD4+ and CD8+ T cell response was noted, with 78% and 71% responders, respectively. IFN-γ and IL-2 dominated the CD4+ T cell response to Gag and Env. The CD8+ response to Gag was broader with expression of IFN-γ, IL-2, MIP-1β and/or CD107. No differences were seen between DNA vaccine groups. Binding antibodies were induced after the second HIV-MVA+/-gp140 in 93% of vaccinees to subtype C Env, with the highest titers among EP/gp140 recipients.Intradermal electroporation of HIV-DNA was well tolerated. Strong cell- and antibody-mediated immune responses were elicited by the HIV-DNA prime and HIV-MVA boosting regimen, with or without intradermal electroporation use.International Standard Randomised Controlled Trial Number (ISRCTN) 60284968

Immunotherapy with an HIV-DNA Vaccine in Children and Adults

Therapeutic HIV immunization is intended to induce new HIV-specific cellular immune responses and to reduce viral load, possibly permitting extended periods without antiretroviral drugs. A multigene, multi-subtype A, B, C HIV-DNA vaccine (HIVIS) has been used in clinical trials in both children and adults with the aim of improving and broadening the infected individuals’ immune responses. Despite the different country locations, different regimens and the necessary variations in assays performed, this is, to our knowledge, the first attempt to compare children’s and adults’ responses to a particular HIV vaccine. Ten vertically HIV-infected children aged 4–16 years were immunized during antiretroviral therapy (ART). Another ten children were blindly recruited as controls. Both groups continued their antiretroviral treatment during and after vaccinations. Twelve chronically HIV-infected adults were vaccinated, followed by repeated structured therapy interruptions (STI) of their antiretroviral treatment. The adult group included four controls, receiving placebo vaccinations. The HIV-DNA vaccine was generally well tolerated, and no serious adverse events were registered in any group. In the HIV-infected children, an increased specific immune response to Gag and RT proteins was detected by antigen-specific lymphoproliferation. Moreover, the frequency of HIV-specific CD8+ T-cell lymphocytes releasing perforin was significantly higher in the vaccinees than the controls. In the HIV-infected adults, increased CD8+ T-cell responses to Gag, RT and viral protease peptides were detected. No augmentation of HIV-specific lymphoproliferative responses were detected in adults after vaccination. In conclusion, the HIV-DNA vaccine can elicit new HIV-specific cellular immune responses, particularly to Gag antigens, in both HIV-infected children and adults. Vaccinated children mounted transient new HIV-specific immune responses, including both CD4+ T-cell lymphoproliferation and late CD8+ T-cell responses. In the adult cohort, primarily CD8+ T-cell responses related to MHC class I alleles were noted. However, no clinical benefits with respect to viral load reduction were ascribable to the vaccinations alone. No severe adverse effects related to the vaccine were found in either cohort, and no virological failures or drug resistances were detected

High plasma levels of soluble Fas in HIV type 1-infected subjects are not normalized during highly active antiretroviral therapy

Plasma levels of soluble Fas (sFas) are elevated in human immunodeficiency virus type 1 (HIV-1) infection, indicating dysregulation of the Fas apoptosis pathway and chronic immune activation. We performed a retrospective study to investigate the effects of HAART on plasma levels of sFas. A cross-sectional study of 27 drug-naive infected subjects and 49 patients under antiretroviral treatment showed that plasma levels of sFas were higher in HIV-1-infected subjects than in 52 HIV-1-negative controls, independently of the treatment status. In a longitudinal study of 69 patients undergoing HAART, we observed a minimal, but significant decrease in sFas plasma levels after 1 year of therapy. Levels of sFas, however, remained still higher than physiologic values. Patients undergoing HAART were further classified as nonresponders or responders on the basis of viremia suppression; no significant changes in plasma levels of sFas were observed between the two groups. These findings show that 1 year of HAART has a minor effect on the sFas levels in plasma. Long-term HAART may be required to normalize the dysregulation of the Fas apoptotic pathway and the persistent immune activation initiated by HIV-1

Optimal Blood Mononuclear Cell Isolation Procedures for Gamma Interferon Enzyme-Linked Immunospot Testing of Healthy Swedish and Tanzanian Subjects▿

Determination of antigen-specific T-cell responses is an important part of vaccine assessment. High levels of recovery, viability, and functionality of peripheral blood mononuclear cells (PBMCs) are essential for reliable assessment of cell-mediated immune responses. Here, we sought to find the cell preparation technique best suited for two clinical vaccine trial sites: Stockholm, Sweden, and Dar es Salaam, Tanzania. Standard Ficoll-Paque gradient centrifugation, BD Vacutainer cell preparation tube (CPT), and Greiner Bio-One LeucoSep tube techniques were tested. Cell yield and viability were recorded. Gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) testing was used to assess cell functionality. No differences in mean recovery or mean viability of fresh PBMCs were observed between Ficoll-Paque gradient centrifugation and CPT techniques as used in Stockholm. In Dar es Salaam, recovery of PBMCs isolated by use of the Ficoll-Paque gradient technique was higher than that seen with CPT (1.58 ± 0.6 versus 1.34 ± 0.4 million cells/ml of blood [P = 0.0469]), and the viability of PBMCs processed by Ficoll-Paque gradient was higher than that seen with CPT-purified cells (95.8% ± 2.3% versus 92.6% ± 4.8% [P = 0.0081]). Furthermore, LeucoSep cell separation gave higher levels of yield (1.10 ± 0.3 versus 0.92 ± 0.3 million cells/ml of blood [P = 0.0022]) and viability (95.7% ± 2.0% versus 93.4% ± 3.2% [P = 0.0012]) than Ficoll-Paque cell separation. The cells purified by the different techniques at the two sites performed equally well in IFN-γ ELISPOT assays. Both techniques generated cell preparations with excellent yield, viability, and functionality in Stockholm. In Dar es Salaam, CPT did not perform as well as Ficoll-Paque separation. In a subsequent comparison, LeucoSep performed better than Ficoll-Paque separation. Our findings emphasize the need for on-site assessment of PBMC purification techniques for optimal evaluation of cell-mediated immune responses

Increased extrafollicular expression of the B-cell stimulatory molecule CD70 in HIV-1-infected individuals

Objective: CD70 molecules expressed by activated T cells provide potent B cell stimulatory signals. We hypothesized that an altered CD70 expression might contribute to B cell abnormalities during HIV-1 infection. Design: CD70 expression and the functional and migratory properties of the CD4+CD70+ T lymphocytes were analyzed in HIV-1-infected patients and in humanized mice. Correlations were tested between CD70 expression and features of B-cell activation, apoptosis sensitivity and functional exhaustion. Methods: CD4+CD70+ T cells were analyzed in cohorts of CD4+ T-cell lymphopenic, viremic or nonlymphopenic, nonviremic HIV-1-infected patients and in noninfected individuals. CD70 upregulation was also followed in HIV-1-infected humanized mice. CD38, CD95, LAIR1 and PD-1 expressions were monitored on B-cell subpopulations, Ki67 was assessed to estimate B-cell proliferation and antibody levels were measured in plasma. Results: Blood CD4+CD70+ T-cell frequencies increased in response to CD4+ T-cell depletion or high viremia levels as a possible consequence of increased activation and proliferation in this subset. CD4+CD70+ T cells produced T-helper 1-type cytokines and expressed chemokine receptors mobilizing toward sites of inflammation but not to lymphoid follicles. High CD70 expression was observed in HIV-1-infected humanized mice at extrafollicular sites (peritoneum, bone-marrow). CD4+CD70+ T-cell frequencies correlated with the expression of the activation marker CD38 and the death receptor CD95 on various memory B-cell subsets, with B-cell proliferation and with plasma IgG levels. Conclusions: CD4+CD70+ T cells may contribute to B cell hyperactivation and accelerated memory B-cell turnover during HIV-1 infection. © Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved