Phylodynamics of the German HIV-1 Subtype A and C epidemic AREVIR - PowerPoint PPT Presentation

Phylodynamics of the German HIV-1 Subtype A and C epidemic AREVIR 06.05.2017 Kirsten Hanke 06.05.2017 1

Distribution of HIV-1 subtypes worldwide The origin and diversity of the HIV-1 pandemic, Hemelaar Trends in Molecular Medicine Volume 18, Issue 3, p182–192, March 2012 2 07.04.2017

Review Subtype A  German subtype A epidemic is attributed to two independent virus variants  Subtype A circulates endemically in Germany since 30 years  13 German clusters from which 6 are still active  Early infections by Eastern African variant among MSM and HET (origin in Kenya, Kongo and Uganda)  1995-2005 strong spread of the Eastern European variant (A FSU ) among PWID  Recent infections mainly by Eastern European variant especially among German MSM  Most recent transmission clusters are German MSM clusters formed after 2013 3

Analysis of Subtype C  147 RKI samples: 92 MolSurv, 48 SC, 6 DS  Sampling period 1992-2016  Reference panel: 442 closely related subtype C sequences retrieved by BLAST search of the Los Alamos HIV database  Bayesian phylogenetic analysis using BEAST v1.8.3 discrete asymmetric diffusion models to infer epidemiological linkage among geographic regions and transmission groups  Multitype-tree Birth-Death and Birth-Death skyline (BDSKY) analyses (BEAST v2.4) to estimate changes in effective reproduction numbers (R e )  AIM : Risk n %  Characterization of the German Subtype C epidemic (e.g. course of the HET 73 50,3 epidemic, origin, affected risk groups) MSM 35 24,1  Identification and characterization of endemic German clades. Dating of their PWID 10 6,9 first common ancestor in Germany  Identification of active clusters showing ongoing transmission events PPI 2 1,4 X 27 17,2 sum 147 100,0 06.05.2017 4

Phylogenetic origin of SubC in Germany: at least 2 subepidemics Second Eastern African 1972 introduction 1968 India Southern African clade 1963 Eastern African clade Brazil 1966 1975 06.05.2017 5

Identification of clades originating in Germany  Criteria:  Clades with posterior probability = 1  At least 3 German subtype C sequences within this clade  the common ancestor is estimated to have introduced infection in Germany Active clades showing ongoing transmission in Germany  Criteria:  at least two infections have occurred within this clade during the last 3 years 06.05.2017 6

German SubC clusters 10 German clusters 4 x HET 4 x MSM; 1 x MSM/HET 1 x Mixed PWID 06.05.2017 7

Phylogenetic origin of German SubC clusters Second Eastern African introduction India Southern African clade Eastern African clade Brazil 06.05.2017 8

German SubC clusters # size tMRCA subclade origin Risk active  10 German Sub C cluster als bunte Tabelle 1 13 2010 South Africa ZW, ZM, MZ PWID (HET/MSM) + 2 7 2004 South Africa ZA MSM + 3 5 2008 South Africa FI, NO, ZA, BW MSM - 4 4 1997 South Africa ZM, ZA, ZW HET - 5 4 2007 South Africa BW, ZA HET - 6 3 2012 (South Africa) DRC, MA MSM + 7 3 2014 Eastern Africa BR MSM/HET + 8 9 2007 Eastern Africa BR MSM + 9 3 2002 Eastern Africa TZ, BI HET - 10 3 2005 Eastern Africa ET, SD HET/PPI +

SubC is increasing again in Germany: Estimation of effective reproduction numbers (R e ) R e : estimates the average number of secondary cases per infectious case in a population made up of both susceptible and non-susceptible hosts. R e R e South African clade R e Eastern African clade HET MSM active inactive PWID

Subtype C is traditionally transmitted by heterosexual contacts HET MSM PWID PPI 06.05.2017 11

Impact of the various transmission routes on the German epidemic Eastern African subclade R e South African subclade R e 06.05.2017 12

Strong increase of PWID mediated infections in I/2016  All PWID infected with subtype C in one cluster  cluster 1, 13 individuals Risk  10 PWID, 1 MSM, 1 HET, 1 unknown  11 male, 2 female (both PWID) 2015  26-42 years old 2010  Nationality: 10 DE, 1 GR, 1 LV, 1 KZ  Country of infection: Germany  First registered infection in Germany: 03/2015  10 individuals sampled between 02-05/2016  tMRCA 2010 or 2015, respectively PWID HET MSM  Area of living: Munich (and Augsburg) 06.05.2017 13

Transmitted SDRM SDRM in all samples (n=589) 5; 1% 559; 17, 3% 34; 6% 94% 10, 2% 1 1 SDRM of RKI samples only (n=147) Sensitive PI NNRTI NRTI PI/NNRTI NNRTI/NRTI 3; 2.0% 134; 14; 9.5% 8; 5.4% 90.5% 2; 1.4% 1; 0.7% Sensitive PI NNRTI NRTI PI/NNRTI

No accumulation of SDRM in German subC clusters NNRTI SDRM NRTI SDRM PI SDRM

Spread of Subtype C to Germany  German subtype C epidemic is attributed to two independent virus variants  10 German clusters from which 6 are still active  Early infections (until early 1990s) mainly by HET Germany transmission (both clades)  1993-2007 drop in subtype C infections  Since 2007 strong increase of infections in both India subclades especially for MSM (but also HET) Ethiopia  Until 2005 no transmission among PWID observed DRC  strong increase in one transmission cluster within Brazil South African subclade in I/2016  Among active clusters are 4 MSM clusters, 1 PWID South Africa cluster and 1 HET cluster (infections occurred in Ethiopia)  MSM clusters in Eastern African subclade are phylogeographically linked with epidemic in Brazil 06.05.2017 17

Comparison with SubA epidemic Subtype A Subtype C Phylogenetic origin of Eastern Africa & Eastern Africa (in part via German epidemic Central/Western Africa + FSU Brazil) & Southern Africa tMRCA (95% HPD) 1953.6 (1951.2-1965) 1963.6 (1956-1967.6) # of German clusters 13 10 # of active clusters 6 6 Risk groups cluster 6 HET, 5 MSM, 2 mixed PWID 4 HET, 4 MSM, 1 mixed (HET/MSM/PWID) HET/MSM, 1 PWID Risk groups current 1 HET, 3 MSM, 2 PWID 1 HET, 4 MSM, 1 PWID epidemic (clusters) TDR in clusters PI TDR in 2 MSM clusters No cluster associated TDRs Sequences analyzed 183 (in total 743) 147 (in total 589) 06.05.2017 18

Outlook  Similar analyses with other nonB subtypes (G, F, CRF01AE and CRF02AG)  Huge subtype B analysis 1983-2017: >5000 sequences 19

Acknowledgments Diagnostic labs: InzSurv/MolSurv HIV-1 Seroconverter RKI – Unit HIV and other RKI - Unit HIV/AIDS, STI and Blood- Retroviruses borne Infections Barbara Gunsenheimer-Bartmeyer Andrea Hauser Viviane Bremer Claudia Kücherer Alexandra Hofmann Karolin Meixenberger Daniel Schmidt Norbert Bannert Bioinformatics Denise Kühnert, Zürich Nuno R. Faria, Oxford Oliver Pybus, Oxford Max von Kleist, Berlin Kaveh Youssef, Berlin 13

Andere Publikationen  ancestral subtype C strain of HIV-1 migrated from Kinshasa to the southern provinces of the Democratic Republic of the Congo (DRC)  migration occurred via major rail networks connecting Kinshasa with southern DRC  ancestral subtype C strain of HIV-1 was introduced into the southern Katanga region of the DRC in the late 1930s (95% HPD 1919 – 1957) then spread independently to east and southern African respectively  tMRCA of the southern African HIV- 1 subtype C epidemic at around 1960 (95% HPD 1956 – 1964), with similar estimates for individual countries within the region  large number of infections were introduced into South Africa via foreign migrants from other southern African nations during the 1970s and 80s  strong periods of epidemic growth during the 1970s and 1980s for the southern African epidemic.  The origin of the subtype C epidemic in the region can be placed around 1960 (95% HPD 1956 – 1964) with strong periods of epidemic growth during the 1970s and 80s for the southern African region and during the 1980s and 90s for South Africa. The periods of strong epidemic growth coincide with periods of socio-political changes in the region during the latter part of the 20 th century. The results from the phylogenetic reconstruction support that migration played an important role in facilitating the introduction and spread of the virus throughout the region and in South Africa in particular. Furthermore, the usage of older sequences provided more accurate estimates of the origin and rate of growth of the epidemic than previous subtype C studies, which used mostly contemporary sequences, further reducing uncertainty in our estimates. (Wilkinson 2015 http://www.nature.com/articles/srep16897)  a substantial proportion of subtype C infections in east Africa resulted from dissemination of a single HIV local variant, probably originated in Burundi during the 1960s. Burundi was the most important hub of dissemination of that subtype C clade in east Africa, fueling the origin of new local epidemics in Ethiopia, Kenya, Tanzania and Uganda. Subtype C lineages of southern African origin have also been introduced in east Africa, but seem to have had a much more restricted spread (Delatorre & Bello, 2012 https://www.ncbi.nlm.nih.gov/pubmed/22848653) 07.04.2017 Lorem ipsum dolor sit 21