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Geoffrey S. Gottlieb, MD PhD Associate Professor Allergy & Infectious Diseases

The Other AIDS Virus: A Brief Overview of HIV-2 infection (Epidemiology, Transmission, Viral Load & Variability). Geoffrey S. Gottlieb, MD PhD Associate Professor Allergy & Infectious Diseases Department of Medicine University of Washington Seattle, USA IAS, Rome 2011 ANRS Satellite:

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Geoffrey S. Gottlieb, MD PhD Associate Professor Allergy & Infectious Diseases

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  1. The Other AIDS Virus:A Brief Overview of HIV-2 infection(Epidemiology, Transmission, Viral Load & Variability) Geoffrey S. Gottlieb, MD PhD Associate Professor Allergy & Infectious Diseases Department of Medicine University of Washington Seattle, USA IAS, Rome 2011 ANRS Satellite: HIV-2: A model of attenuated HIV Infection

  2. HIV-2: Discovery/Origins • 1985: serum from Senegalese FSW cross-reacts with SIVmac.(Barinet al. Lancet 1985) • 1986: HIV-2 isolated from AIDS patients in Guinea- Bissau and Cape Verde. (Clavelet al.Science 1986) • Retrospective look shows HIV-2 in stored serum from 1960s in West Africans and Portuguese Nationals who visited West Africa in the 1960s. (Kawamura et al. Lancet. 1989, Brycesonet al. Lancet 1988.) • Phylogenetic dating HIV-2 introduction in humans to 1930-40s (Lemeyet al. PNAS 2003, Wertheim et al. PloS Comp Bio 2009.)

  3. A global view of HIV infection 33.4 million people [31.1‒35.8 million] living with HIV, 2009 >25 million deaths HIV-2 Epidemiology (I) No WHO estimate of HIV-2 infections 2.4

  4. HIV-2 Epidemiology (II) Countries reporting HIV-2 infections Sources: Pubmed & LANL

  5. HIV-2 Epidemiology (III) Arienet al. JVI 2005 Prevalence of HIV-2 in Sub-Saharan Africa?

  6. HIV-2 Epidemiology (IV) HIV-2 Seroprevalence in the 1980-90s Source: US Census Bureau

  7. Senegal Prevalence Incidence Guinea-Bissau Hamel et al. ARHR 2007 The Gambia Masson et al. STI 2007 van derLoeffet al. IJE 2006 Bruhn & Gilbert Lancet ID 2011

  8. HIV-2: Molecular Epidemiology & Variability • HIV-2: 8 groups : A-H • Groups A and B most common • Group A-B recombinants reported rarely • Groups C-H have only been isolated very rarely • Closely related to SIVsm (Sooty mangabey, Cercocebusatys) • Each HIV-2 group probably represents a separate zoonotic transmission from Sooty mangabeys to humans • Similar to HIV-1 groups • M, N, O (chimps) • P (gorillas?)

  9. Sooty mangabey (Cercocebusatys) www.bushmeat.org

  10. Phylogenetic Relationship of HIV-2, HIV-1 & SIVs Santiago et al. JVI 2005 Los Alamos HIV Database

  11. HIV-2 groups (subtypes) in HIV- Database (LANL) (accessed JAN-2010)

  12. HIV-2 Transmission & Genital Tract Shedding • Modes of HIV-2 transmission same as HIV-1 • Sexual (F<->M, MSM), IDU, MTCT, Blood borne • Sexual Transmission HIV-2 << HIV-1 (Kankiet al. Lancet 1994) • Risk estimates: HIV-1: 3-4 fold greater than HIV-2. • MTCT transmission HIV-2 << HIV-1(Matheronet al. Lancet 1990; Adjorlolo-Johnson et al. JAMA 1994) • ~0-4% for HIV-2 vs ~25-35% for HIV-1 • Male & Female genital tract shedding HIV-2 << HIV-1 (Gottlieb et al. AIDS 2006, Hawes et al. AIDS 2008) Senegal-Males at SMIT CHU Fann Senegal- FSW Gilbert et al. Stat Med. 2003 Gottlieb et al. AIDS 2006

  13. HIV-2 Natural History & Clinical Outcomes • HIV-2 infection causes AIDS (Brun-Vezinetet al. Lancet. 1987; Clavelet al. NEJM 1987; many others) • HIV-2 is generally less pathogenic/virulent than HIV-1 (Marlinket al. Science 1994; many others) • Most HIV-2 patients are “long term non-progressors” (LTNP) • Longer asymptomatic stage • Slower decline in CD4 count • Lower mortality rate due to AIDS MTCT Adults Mortality hazards compared to HIV-negative HIV-1=9.9 (95% CI 5.2–19) HIV-2=3.9 (95% CI, 1.2–12) Hansmannet al. JAIDS 2005 Schim van derLoeffet al. AIDS 2003

  14. Clinical Manifestations of HIV-2 infection • OI’s & AIDS-associated malignancies are generally similar to those reported for HIV-1 • OI’s & AIDS-AM in HIV-2 may occur at higher CD4 counts than HIV-1 (Martinez-Steele et al. AIDS 2007) • Due to slower CD4 cell loss? • Kaposi’s Sarcoma may occur less frequently in HIV-2 (Ariyoshiet al. J Hum Virol. 1998) • Invasive cervical cancer, severe CMV disease, HIV encephalitis and cholangitis may occur more frequently in HIV-2 infected individuals. (Hawes et al. JID 2003, Lucas et al. AIDS 1993) Survival after AIDS Dx. in The Gambia Martinez-Steele et al. AIDS 2007

  15. HIV-2: Diagnosis & Testing Screening: HIV-1/HIV-2 ELISA/EIA Confirmation: “Rapid” tests that distinguish HIV-2 from HIV-1: Immunocomb II, Multispot, Genie II, SD Bioline HIV-2 EIA HIV-2 western blot HIV-2 viral load testing Not commercially available or US-FDA approved Generally not available in RLS Collaborative efforts to standardize and QA/QC HIV-2 through the ACHI EV2E network. (Damondet al. JCM 2008 & 2011) (http://etudes.isped.u-bordeaux2.fr/achiev2e/)

  16. HIV-2 viral loads • HIV-2 Plasma RNA << HIV-1 (Simon et al. AIDS 1993, De Cock et al. JAMA 1993, many others) • ~25% have “undetectable” plasma RNA (<50-100 copies/ml) • Model for “elite control”? • HIV-2 PBMC DNA ~ HIV-1 Senegal Cohort French HIV-2 Cohort HIV Plasma RNA HIV PBMC DNA Thiébautet al. AIDS 2011 Gottlieb et al. JID 2002

  17. HIV-2 plasma RNA viral load predicts CD4 decline & disease progression. Gottlieb et al. JID 2002-Senegal Mortality hazard rate increased by 2.12 for each log10 increase in RNA load (95% CI, 1.3–3.5; p = 0.0023) Schim van derLoeffet al. Retrovirology 2010 Guinea-Bissau Ariyoshiet al. AIDS 2000 The Gambia

  18. Dual HIV-1/HIV-2 seropositivity & infection • Dual HIV-1/HIV-2 infection first reported in 1980’s (Rayfieldet al. JID 1988) • Difficult to differentiate cross-reactive serology from true infection without HIV-1 and HIV-2 specific PCR. • ~40-80% of dual-sp confirmed dually infected, depending on the screening algorithm and PCR methods. (Walther-Jallowet al. ARHR 1999, Rouetet al. JCM 2004) • Prevalence of Dual-SP/I is ~5-15% of HIV cases in West Africa • Dual Infection order: Co-infection? or Super-infection • HIV-1 -> HIV-2 -> dual • HIV-2 -> HIV-1 -> dual • Correct Assessment has implications for ART & biologic-immunological studies.

  19. Does HIV-2 protect against HIV-1? • Senegalese CSW w/ HIV-2 have a RR= 0.32 of subsequent acquisition of HIV-1 (Travers et al. Science 1995) • Subsequent studies conducted in Guinéa-Bissau (Aabyet al. 1997; Norrgrenet al.1999, van derLoeffet al. 2001), and the Ivory Coast (Wiktoret al.1999), did not show any protective effect.

  20. Does HIV-1/HIV-2 dual infection affect disease course? • In vitro: HIV-1/HIV-2 super-infection interference (Hartet al. 1990, Le Guernet al. 1992, von Dalnoket al. 1993) and transcriptional inhibition (Aryaet al. 1996, Al-Harthiet al. 1998, Browninget al. 1999) • In vivo: HIV-2 pro-viral loads < in dually infected patients (Sarret al. 1999), HIV-1 RNA viral loads lower in dually infected patients (Andersson et al. 2000, Alabi et al. 2003, Hawes et al. -unpublished) • Mortality: HIV-1 ~ HIV-1/HIV-2 duals >> HIV-2 (Schim van derLoeff et al. AIDS 2002, Holmgren et al. Retrovirology 2007, Alabi et al. 2003)

  21. Summary: • HIV-2 prevalence, disease progression & transmission are significantly less than HIV-1. • HIV-2 “attenuation” is likely due to lower HIV-2 RNA viral loads. • The underlying mechanisms that lead to low HIV-2 RNA viral loads remains to be determined… • Determination of the underlying HIV-2 disease mechanisms may provide further insight into HIV-1 disease control.

  22. Senegal Papa Salif Sow Macoumba Toure Selly Ba Cheikh Tidiane Ndour Mery Dia Badiane Louise Fortes Jacques Ndour Fatou Niasse Fatou Traore Habibatou Diallo Agne Ndeye Rokhaya Fall Sophie Chablis Marie Pierre Sy Mame Dieumba Mbaye Ndoye Khady Diop Fatima Sall Amadou Bale Diop Cheikh Gueye Boubacar Diamanka Marianne Ndiaye Marie Cisse Thioye Fatou Cisse Madeleine Mbow Marianne Fadam Diome Marie Diedhiou UW Nancy Kiviat Steve Hawes Donna Kenney Steve Cherne Josh Stern QinghuaFeng Bob Smith Dana Raugi Charlotte Pan BerukAsfaw Brad Church Matt Coyne Alexandra Hernandez Kara Parker Bob Coombs Ming Chang Joan Dragavon Jim Mullins UW-Dakar HIV-2 Study Group

  23. GrazieThank you Funding: Royalty Research Fund

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