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

<p>Abstract</p> <p>Background</p> <p>Our 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.</p> <p>Methods</p> <p>A random sample of 861 HIV-1-infected patients attending HIV clinics at King's and St Thomas' hospitals' were subtyped using an in-house enzyme-linked immunoassay and <it>env </it>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.</p> <p>Results</p> <p>Complete 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)</p> <p>Conclusions</p> <p>This 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.</p

The HIV-1 Subtype C Epidemic in South America Is Linked to the United Kingdom

Background: The global spread of HIV-1 has been accompanied by the emergence of genetically distinct viral strains. Over the past two decades subtype C viruses, which predominate in Southern and Eastern Africa, have spread rapidly throughout parts of South America. Phylogenetic studies indicate that subtype C viruses were introduced to South America through a single founder event that occurred in Southern Brazil. However, the external route via which subtype C viruses spread to the South American continent has remained unclear.Methodology/Principal Findings: We used automated genotyping to screen 8,309 HIV-1 subtype C pol gene sequences sampled within the UK for isolates genetically linked to the subtype C epidemic in South America. Maximum likelihood and Bayesian approaches were used to explore the phylogenetic relationships between 54 sequences identified in this screen, and a set of globally sampled subtype C reference sequences. Phylogenetic trees disclosed a robustly supported relationship between sequences from Brazil, the UK and East Africa. A monophyletic cluster comprised exclusively of sequences from the UK and Brazil was identified and dated to approximately the early 1980s using a Bayesian coalescent-based method. A sub-cluster of 27 sequences isolated from homosexual men of UK origin was also identified and dated to the early 1990s.Conclusions: Phylogenetic, demographic and temporal data support the conclusion that the UK was a crucial staging post in the spread of subtype C from East Africa to South America. This unexpected finding demonstrates the role of diffuse international networks in the global spread of HIV-1 infection, and the utility of globally sampled viral sequence data in revealing these networks. Additionally, we show that subtype C viruses are spreading within the UK amongst men who have sex with men

Molecular Phylodynamics of the Heterosexual HIV Epidemic in the United Kingdom

The heterosexual risk group has become the largest HIV infected group in the United Kingdom during the last 10 years, but little is known of the network structure and dynamics of viral transmission in this group. The overwhelming majority of UK heterosexual infections are of non-B HIV subtypes, indicating viruses originating among immigrants from sub-Saharan Africa. The high rate of HIV evolution, combined with the availability of a very high density sample of viral sequences from routine clinical care has allowed the phylodynamics of the epidemic to be investigated for the first time. Sequences of the viral protease and partial reverse transcriptase coding regions from 11,071 patients infected with HIV of non-B subtypes were studied. Of these, 2774 were closely linked to at least one other sequence by nucleotide distance. Including the closest sequences from the global HIV database identified 296 individuals that were in UK-based groups of 3 or more individuals. There were a total of 8 UK-based clusters of 10 or more, comprising 143/2774 (5%) individuals, much lower than the figure of 25% obtained earlier for men who have sex with men (MSM). Sample dates were incorporated into relaxed clock phylogenetic analyses to estimate the dates of internal nodes. From the resulting time-resolved phylogenies, the internode lengths, used as estimates of maximum transmission intervals, had a median of 27 months overall, over twice as long as obtained for MSM (14 months), with only 2% of transmissions occurring in the first 6 months after infection. This phylodynamic analysis of non-B subtype HIV sequences representing over 40% of the estimated UK HIV-infected heterosexual population has revealed heterosexual HIV transmission in the UK is clustered, but on average in smaller groups and is transmitted with slower dynamics than among MSM. More effective intervention to restrict the epidemic may therefore be feasible, given effective diagnosis programmes

Future Military Force Possibilities Study, 2001-2021: Korea, Australia, Japan: a Strategic Decision of National Security Evolution.

This study describes the evolution of a possible future for Asia 2001-2021. It envisions the realization of two longstanding US goals: peaceful political unification of Taiwan and the People’s Republic of China, and, peaceful Korean unification. Nothing dramatic occurs on the global front, no major wars break out, and both economic and technological change are evolutionary rather than revolutionary. In short, we develop an example of what Herman Kahn called a “surprise free” scenario. The officer-students in the first class of the Systems Engineering and Integration (SEI- 1) curriculum developed the above scenario in detail for Korea, Australia and Japan. They are responsible for Chapters 3, 4 and 5, which describe the evolution of Korean unificationAustralian efforts to cement protective relations with the United States and others with interests in a peaceful, free Asiaand the “coming out of the penalty box” by Japan as she rides her reinvigorated economy and takes increasing responsibility for her own defense

Development of an env gp41-Based Heteroduplex Mobility Assay for Rapid Human Immunodeficiency Virus Type 1 Subtyping

The gp120 region of the human immunodeficiency virus type 1 (HIV-1) envelope (env) gene exhibits a high level of genetic heterogeneity across the group M subtypes. The heteroduplex mobility assay (HMA) has successfully been used to assign subtype classifications, but C2V5 primers often fail to amplify African strains. We developed an env gp41-based HMA for which the target sequence is amplified with highly conserved gp41 primers, known to efficiently amplify nucleic acids from HIV-1 group M, N, and O viruses. By using gp41 from a new panel of reference strains, the subtype assignments made by our modified HMA were concordant with those obtained by sequencing and phylogenetic analysis of 34 field strains from 10 countries representing subtypes A to G. Testing of field strains from Nigeria further demonstrated the utility of this modified assay. Of 28 samples, all could be amplified with gp41 primers but only 17 (60.7%) could be amplified with the standard C2V5 primers. Therefore, gp41-based HMA can be a useful tool for the rapid monitoring of prevalent subtypes in countries with divergent strains of circulating HIV-1