Transcript What*s new with HIV-2?

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
HIV-2: Discovery/Origins
• 1985: serum from Senegalese FSW cross-reacts
with SIVmac. (Barin et al. Lancet 1985)
• 1986: HIV-2 isolated from AIDS patients in GuineaBissau and Cape Verde. (Clavel et 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, Bryceson et al. Lancet 1988.)
• Phylogenetic dating HIV-2 introduction in humans to
1930-40s (Lemey et al. PNAS 2003, Wertheim et al. PloS Comp Bio 2009. )
HIV-2 Epidemiology (I)
A global view of HIV infection
33.4 million people [31.1‒35.8 million] living with HIV, 2009
>25 million deaths
No WHO estimate of HIV-2 infections
2.4
HIV-2 Epidemiology (II)
Countries reporting HIV-2 infections
Sources: Pubmed & LANL
HIV-2 Epidemiology (III)
Arien et al. JVI 2005
Prevalence of HIV-2 in Sub-Saharan Africa?
HIV-2 Epidemiology (IV)
HIV-2 Seroprevalence in the 1980-90s
Source: US Census Bureau
Senegal
Prevalence
Incidence
Guinea-Bissau
Hamel et al. ARHR 2007
The Gambia
Masson et al. STI 2007
van der Loeff et al. IJE 2006
Bruhn & Gilbert Lancet ID 2011
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,
Cercocebus atys)
• 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?)
Sooty mangabey
(Cercocebus atys)
www.bushmeat.org
Phylogenetic Relationship of HIV-2, HIV-1 & SIVs
Santiago et al. JVI 2005
Los Alamos HIV Database
HIV-2 groups (subtypes) in HIV- Database (LANL)
(accessed JAN-2010)
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 (Kanki et al. Lancet 1994)
– Risk estimates: HIV-1: 3-4 fold greater than HIV-2.
• MTCT transmission HIV-2 << HIV-1 (Matheron et 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- FSW
Senegal-Males at SMIT CHU Fann
Gilbert et al. Stat Med. 2003
Gottlieb et al. AIDS 2006
HIV-2 Natural History & Clinical Outcomes
• HIV-2 infection causes AIDS (Brun-Vezinet et al. Lancet. 1987; Clavel et al. NEJM
1987; many others)
• HIV-2 is generally less pathogenic/virulent than HIV-1 (Marlink et
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)
Schim van der Loeff et al. AIDS 2003
Hansmann et al. JAIDS 2005
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 (Ariyoshi et 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
HIV-2: Diagnosis & Testing
1.
Screening:
• HIV-1/HIV-2 ELISA/EIA
2. 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 HIV2 through the ACHI EV2E network.
(Damond et al. JCM 2008 & 2011)
(http://etudes.isped.u-bordeaux2.fr/achiev2e/)
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
HIV Plasma RNA
HIV PBMC DNA
French HIV-2 Cohort
Thiébaut et al. AIDS 2011
Gottlieb et al. JID 2002
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)
Ariyoshi et al. AIDS
2000
Schim van der Loeff et al. Retrovirology 2010
Guinea-Bissau
Dual HIV-1/HIV-2 seropositivity & infection
• Dual HIV-1/HIV-2 infection first reported in 1980’s
(Rayfield et 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-Jallow et al. ARHR 1999, Rouet et 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.
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 (Aaby et al. 1997; Norrgren et al. 1999, van der Loeff et
al. 2001), and the Ivory Coast (Wiktor et al. 1999), did
not show any protective effect.
Does HIV-1/HIV-2 dual infection
affect disease course?
• In vitro: HIV-1/HIV-2 super-infection
interference (Hart et al. 1990, Le Guern et al. 1992, von Dalnok et al. 1993) and
transcriptional inhibition (Arya et al. 1996, Al-Harthi et al. 1998, Browning
et al. 1999)
• In vivo: HIV-2 pro-viral loads < in dually
infected patients (Sarr et 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 >> HIV2 (Schim van der Loeff et al. AIDS 2002, Holmgren et al. Retrovirology 2007, Alabi et al. 2003)
Summary:
• HIV-2 prevalence, disease progression &
transmission are significantly less than HIV-1.
• HIV-2 “attenuation” is likely due to lower HIV2 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.
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-Dakar HIV-2 Study Group
UW
Nancy Kiviat
Steve Hawes
Donna Kenney
Steve Cherne
Josh Stern
Qinghua Feng
Bob Smith
Dana Raugi
Charlotte Pan
Beruk Asfaw
Brad Church
Matt Coyne
Alexandra Hernandez
Kara Parker
Bob Coombs
Ming Chang
Joan Dragavon
Jim Mullins
Grazie
Thank you
Funding:
Royalty Research Fund