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HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
HIV Clade Diversity and Neuropathogenesis
Davey Smith, M.D., M.A.S.Assistant Professor of Medicine
University of California San DiegoVeterans Affairs Medical Center, San Diego
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Why might the virus matter?1. HIV-1 genome is approximately 9800 base
pairs long and human genome is 3 billion.2. The genetic difference between any two
people is <0.01%. 3. The genetic difference between two strains
of HIV can be as much as 30 or 40% in certain coding regions, such as env.
4. Allows evasion of host immune responses and antiretroviral therapy.
5. Neurocognitive functioning: • Clade B vs non-clade B
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
HIV Family Tree
Retroviruses. Cold Spring Harbor Laboratory Press; c1997. Van Heuverswyn F. et al Nature. 2006 Nov 9;444(7116):164. Kober et al. Science 2000.
(1809-1940)
(1915-1941)
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
HIV-1 Group M Family
lanl.gov (2007)
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Clade Evolution General Area Clades 1990 Clades 1997 Clades 2007 Africa A, B, C, D, E, G, H, O A, B, C, D, E, F, G, H, O Brazil B, C, F B, C, E, F China B, E B, E India A, B, C A, B, C Romania F A, B, C, D, E, F United States B A, B, D, E, O
Virtually all clades and CRFs are represented
on every Continent (except maybe Antartica).
lanl.gov (2007)
If you look for it…
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Circulating Clades in Oceania
93% B
80% B20% C
www.hiv.lanl.gov (2007)
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Circulating Clades in Asia
www.hiv.lanl.gov (2007)
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Clades in Asia
www.hiv.lanl.gov (2007)
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Evaluation of Three Recombination Breakpoint Analysis Programs, using HIV-1 as an Example Genome. 39.769 Presentation - Allison M. Land
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Recombinant FormsCirculating Recombinant Forms (CRFs)
19 CRFs25% of all new HIV infections in Europe
Unique Recombinant Forms (URFs)10% of all new HIV infections in Africa
McCutchan et al. JV 2005
SI
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Clade Phenotype Differences
Phenotype Clades Potential Mechanism Disease Progression D>C>A>B>G
B>D>A,C Env binding to CD4 X4>R5 Tropism
Transmission B: MSM, IDU A/E, C: MSW, WSM C>D>A: MTCT
Env diversity (blood vs. mucosal)
Treatment Different resistance pathways Pol diversity Neuropathogenesis B>C, A? A/E?, D? Tat diversity
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Adapted Ellis Venice 2007
Tat activationNF-kB bindingCellular tropism
Truncated in clade DTruncated
in clade C
Enlarged in clade C
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
HIV associated dementiaRole of Tat as a monocyte-chemokine
Tat can recruit monocytes:
1. Directly2. Indirectly through
Astrocytes in an MCP-1-mediated fashion.
Disruption of the CC motif in clade C?
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Serine or Histidine at position 300 of gp120 (5 of V3 loop) assoc w severity of neurocognitive impairment
From Pillai et al, Brain ‘06
Worse
cognitionB
ettercognition
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Frequency of serine 300 substitution by clade
1. Clade B - 10%2. Clade A - <1 to 6%3. Clade C - 5%, 4. Clade D - 11%
Pillai, Wong, personal communication
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
How to evaluate clade effect on neurocognitive functioning
1. Standardized NP measurements with norms• Same population with multiple clades• Multiple populations with same clades• Multiple populations with multiple clades
2. Clade typing of more than one appropriate coding region to evaluate for recombinant forms
3. Account for co-factors4. Characterize “signature sequence”5. Characterize phenotype
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