HIV Clade Diversity and Neuropathogenesis - UNC … Clade Diversity and Neuropathogenesis Davey Smith, M.D., ... an Example Genome. 39.769 Presentation ... Disease Progression D>C>A>B>G

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


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 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-1 Group M Family

lanl.gov (2007)


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…


Circulating Clades Globally


Circulating Clades in Oceania

93% B

80% B20% C

www.hiv.lanl.gov (2007)


Circulating Clades in Asia



Clades in Asia



Evaluation of Three Recombination Breakpoint Analysis Programs, using HIV-1 as an Example Genome. 39.769 Presentation - Allison M. Land


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




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


Adapted Ellis Venice 2007

Tat activationNF-kB bindingCellular tropism

Truncated in clade DTruncated

in clade C

Enlarged in clade C


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?


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


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


Blaming it all on the clade?


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


Acknowledgements


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HIV Clade Diversity and Neuropathogenesis - UNC … Clade Diversity and Neuropathogenesis Davey Smith, M.D., ... an Example Genome. 39.769 Presentation ... Disease Progression D>C>A>B>G