The role of virus and host factors in HIV transmission

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The role of virus and host factors in HIV
transmission
Host factors
Viral factors
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The role of virus and host factors in HIV
transmission
Host factors
Characterization of these factors may allow us to
manipulate or mimic those that play a role in
blocking infection
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I. Host genetic factors.

• Mutations in the primary HIV-1 coreceptor, CCR5

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II. Modifiable host factors.

• In contrast to host genetics, these factors are
  ones that could potentially be altered by
  interventions.
• Presence of a sexually transmitted disease
• Both ulcerative and non ulcerative
• viral (e.g. HSV-2) and bacterial (e.g. Neisseria
  gonorrhoeae)
• In men, lack of circumcision
• In women, hormonal contraception use (?)

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Innate Antiviral Factors.

• Proteins present in some cells that block HIV-1
  replication in those specific cell types.
• Restriction factors TRIM5?, APOBEC3G

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HIV-1 has a very effective way to counter
APOBEC3G the Vif protein.
Vif blocks incorporation of APOBEC3G into viral
particles
Vif
APOBEC
Producer Cell
Target cell
Malim lab
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The challenges and opportunities

• Natural antiviral factors provide a window
  into the vulnerable points of HIV-1.
• We may be able to use this information to design
  new therapies to block HIV-1 infection
• By findings ways to keep Vif from countering the
  natural human antiviral protein, APOBEC3G.
• By mimicking TRIM5a proteins that naturally
  block HIV-1, such as TRIM5a found in macaque
  monkeys.

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One of the first case reports of superinfection
(Jost et al. NEJM 2002 ) First infection was
with subtype AE virus a second infection with
subtype B virus was 2.5 years later

AE
2.5 years
Other early case reports Atfield Nature, 2002,
Ramos J. Virol. 2002, Koelsch AIDS 2003
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Are these rare cases, or is re-infection by HIV-1
common?

• There is limited data that addresses the risk
  of re-infection, or defines when re-infection
  occurs after the first infection.

CTL Antibody
Time PI
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Are these rare cases, or is re-infection by HIV-1
common?

• There is limited data that addresses the risk
  of re-infection, or defines when re-infection
  occurs after the first infection.

CTL Antibody
Time PI

• If superinfection occurs late into the first
  infection, it may be doing so despite immune
  response to the first HIV strain

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We have begun to examine the incidence and timing
of superinfection in a prospective HIV-1 negative
cohort in Mombasa, Kenya (1993-present)
The time of the first infection has been define
by regular serology and RNA testing


Antibody
Virus
There are 80 women with gt 5 years of follow-up
after the first infection
Seattle/Kenya collaboration
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We have examined 57 cases in the Mombasa cohort
For cases where we see sequence differences that
suggest re-infection, we analyze sequences in
between using multiple methods.
Plasma viral levels (RNA copies/ml)
1-6 mos PI
3-5 years PI
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Summary of detailed analyses of one case Initial
infection with subtype D Superinfection by
subtype A HIV-1
0.0
264
559
0
70
385
1790
105
987
765
0
50
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2282
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Subtype
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Estimated time of infection for this case of
intersubtype superinfection
1 2 3 4
5
Years PI
Intersubtype
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Estimated time of infection for the eight
potential cases of superinfection observed among
57 women in the Mombasa cohort
1 2 3 4
5
Years PI
Intersubtype Intrasubtype
The intervals are variable due to differences in
availability of samples for testing.
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Estimated time of super-infection including
published cases where estimates of when the
second virus infected are available.
1 2 3 4
5
Years PI
Intersubtype Intrasubtype
Atfield 2002 Jost, 2002 Ramos 2002 Koelsch
AIDS 2003 Gottlieb, 2004 Yearly, 2004 Chohan,
2005 Smith 2004 Yang 2005 unpublished
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Superinfection has been detected throughout the
first several years after initial HIV-1 infection.
1 2 3 4
5
Years PI
Intersubtype Intrasubtype
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The challenges and opportunities

• To determine if HIV infection reduces the risk
  of subsequent HIV acquisition, and if so when.
• In those who become superinfected, what immune
  responses are lacking or impaired?
• Those that are lacking may be important immune
  responses to elicit in vaccination
• Those that are present are ones that probably
  are not important responses for developing an
  effective vaccine.
• To define the clinical consequences of
  superinfection so that HIV people can be fully
  informed regarding the impact of re-infection on
  their disease progression.

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The role of virus and host factors in HIV
transmission
Viral factors
Characterization of these factors may allow us to
identify an Achilles heel in the virus to target
with a vaccine or microbicide
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I. Virus factor viral load Higher viral burden
in the index case increases the chance of
transmission
High viral load
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Exposure to lower levels of virus is associated
with a reduced risk of infection
Low viral load
Lower risk of infection
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Viral factors that influence risk of
transmission.

• This has been shown for heterosexual
  transmission in discordant couples as well as in
  the setting of MTCT.
• Most studies have focused on cell-free virus
  levels (viral RNA) in plasma.

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Is it the cell-free form of the virus what is
most important in transmission?
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Both cell-free and cell-associated HIV levels in
breast milk have been shown to correlate with
MTCT. Cell-associated virus remains an important
correlate even after controlling for cell-free
virus levels
Non transmitting Transmitting
Adjusted p 0.002
1.67
1.11
Cell-associated BM levels (Log10 BM cell DNA/106
cells)
Seattle/Kenya collaboration Rousseau, JID 2004
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The challenges and opportunities

• Recent studies suggest that in breast milk, ARVs
  may have less effect on reducing cell-associated
  virus than cell-free virus (Shapiro JID, 2005
  Lehman unpublished).
• Thus, if we want to predict the impact of ARVs
  on transmission risk, we need to know whether
• cell-free or cell-associated virus is more
  important in transmission
• how different ARVs impact both types of virus in
  relevant compartments.

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II. Virus factors Features of the virus itself

• The virus variants that are transmitted are a
  small subset of those present in the index case,
  suggesting there is a bottleneck during
  transmission

Transmission bottleneck
Chronic infection Recent infection
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Viruses that use CXCR4 for entry appear to be
less favored for transmission
CXCR4
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Transmitted viruses tend to be among those with
less glycosylation on their envelope protein
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Selection for less glycosylated viruses was first
illustrated in a study of 8 initially discordant
couples comparing viral envelope sequences from
the donor and the recipient
Plt0.0001 Mann Whitney
of glycosylation sites
Donor variants
Recipient variants
N 146
N 101
Cumulative data from 8 heterosexual transmission
pairs, 247 envelopes Derdeyn, et al Science 2004
(UAB/Zambia project)
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This has also been shown for mother-infant
transmission in a study of 12 pairs who were
part of the Nairobi breastfeeding clinical trial.

3
0
P 0.004 (GEE model)
2
5
of glycosylation sites
2
0
1
5
Mother variants
Infant variants
N 64
N 32
Cumulative data from 12 mother-infant pairs, 96
envelopes Wu, et al J Virol. 2006
(Seattle/Kenya project Nairobi breastfeeding
trial)
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Selection for viruses with less glycosylation has
been observed in several studies, but we do not
yet know the biological basis for this selection
Plasma viral levels (RNA copies/ml)
Less glycosylated
More glycosylated
Viral load
Time
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The challenges and opportunities

• Why are viruses with fewer glycosylation sites
  favored for transmission?
• Do they have an Achilles heel?
• If certain viruses are more successful at
  spreading, then it is critical that candidate
  interventions that target the virus be tested
  against such strains.
• Particularly relevant for screening microbicides
  and vaccines

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The challenges and opportunities

• We need better animal model systems that mimic
  these transmitted strains.
• Currently used viruses are not likely to
• be good models (e.g. SHIV89.6 SIVmac).

SHIV encoding a subtype C HIV-1 envelope from an
infant early in infection Ruprecht and
colleagues, in press.
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The challenges and opportunities overview

• There is still much to be learned about the
  host and viral factors that contribute to
  defining the risk of HIV infection.
• Recent discoveries (restriction factors,
  glycosylation patterns) provide new insights into
  potential vulnerabilities of the virus.
• Other studies, such as those suggesting that
  superinfection may be common, may force us to
  reassess some of our old notions.

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Fred Hutchinson Research Center University
of Nairobi
Bhavna Chohan Anne Piantadosi Xueling
Wu Stephanie Rainwater Sandy Emery Christine
Rousseau Dana Panteleeff Dara Lehman
Ruth Nduati Dorothy Mbori-Ngacha Walter Jaoko J.
Ndinya Achola
Ruth Nduati, Dorothy Mbori Ngacha, J. Ndinya
Achola, Walter Jaoko The Nairobi Breast Feeding
trial team
Joan Kreiss, Grace John Stewart Scott McClelland
, Barb Richardson, Carey Farquar
Ludo Lavreys Kishor Mandalyia Varsha
Chohan Clinic lab staff
Bhavna Chohan Anne Piantadosi Xueling
Wu Stephanie Rainwater Dana Pantaleeff Sandy
Emery
Ganjoni Clinic
Coast Hospital Ganjoni Clinic University of
Washington