(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

• 1985: serum from Senegalese FSW cross-reacts with SIVmac.
(Barin et al. Lancet 1985)
• 1986: HIV-2 isolated from AIDS patients in Guinea-
Bissau 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

Prevalence
Senegal
Incidence
Hamel et al. ARHR 2007
The Gambia van der Loeff et al. IJE 2006
Guinea-Bissau
Masson et al. STI 2007
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
Los Alamos HIV Database
Santiago et al.
JVI 2005

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-Males at SMIT CHU Fann
Senegal- FSW
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

• 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

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 HIV-
2 through the ACHI
E
V
2E network.
(Damond et al. JCM 2008 & 2011)
(http://etudes.isped.u-bordeaux2.fr/achiev2e/)

• 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
Gottlieb et al.
JID 2002
Thiébaut et al . AIDS 2011

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

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.

• 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.

• In vitro : HIV-1/HIV-2 super-infection interference
(Hart e t 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 e t al.
2000, Alabi e t al. 2003, Hawes e t al. -unpublished)
• Mortality: HIV-1 ~ HIV-1/HIV-2 duals >> HIV-
2
(Schim van der Loeff e t al. AIDS 2002, Holmgren e t al. Retrovirology 2007, Alabi e t al. 2003)

• 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.

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