natural history of typical hiv infection

1. Natural History of a Typical HIV
Infection
Florence
Prof Nduati
http://bmj.bmjjournals.com/cgi/content/f
ull/322/7297/1290

2. Typical HIV Infection
 median incubation period for AIDS is around
10 years(adults and children inrected arrter
sexual abuse) in fetus fulminant disease dev
in 2-3 yrs
 progression to AIDS occurs with increase in
viral load and destruction of T4-helper
lymphocytes
 Three phases of host and virus interaction
exist: acute RV syndrome and chronic phase
and full blown AIDs

3. HIV in children
 Fetuses and new borns have poorly
functioning complement adaptive and
phagocytic immune systems
 Differentiation of B and T lymphocytes
occurs after 10 weeks of dev in utero,
HIV infection can occur before then
 HIV DNA found in splenic and thymic
specimens of fetuses at 10wks in utero

4. 

5. Acute retroviral Syndrome
 Characterized by high levels of vx production,
viraemea and seeding of lymphoid tissue
 Immune response dev.
 40% to 90% dev viral syndrome 3 t 6 weeks
later and resolve spontaneously in 2 to 4 wks
 Non specific symptoms occur : sore
throat,myalgia,fever rash,wt
loss,fatigue,cervical adenopathy,diarrhea,and
vomiting

6. Chronic phase
 Relative viral containment of virus
 Virus replicates predominantly in the
lymphoid tissues
 Patients are asymptomatic or Persistent
LPD dev
 Minor opportunistic infections may occur
Oral thrush, herpes zoster and
thrombocytopenia

7. Chronic Phase
 Marked by increase in viral load, onset of
fever > 1/12, fatigue, wt loss, and diarrhea,
opportunistic infections,secondary neoplasia
and clinical neurological disease
 In the absence of treatment chronic infection
progresses to AIDs
 Exceptions to above course are long term
and rapid progressors

8. Long term non progressors
 Untreated cases who remain
assymptomatic for more than 10 yrs
 CD4s within normal range, clinically
stable, low viraemea ,normal immune
system, normal lympocyte architecture
and appearance

9. Factors associated with long term
survival
 One cohort the survivors had defect virus
genome -- nef gene which down regulates
CD4 and MHC1 expression, blocks
apoptosis, enhances virion infectivity
 Associted with HLA B5701 and HLA B2705..
HLA heterozygozity of class 1 loci is
asscociated with long term survival

10. Factors associated with long term
survival
 Host factors such as heterozygosity for the
CCR5-32 deletion. CCR5 associated with
slow prog. Polyphormism of CCR5 is assco
with slow progression
 Heterozigosity for CCR2 641 mutation. CCR2
641 dimerises with CXCR4 reducing the
availability of these receptors for the X4
viruses

11. Factors associated with long term
survival
 Homozygosity for SDF1 mutation may
up regulate SDF1 the natural ligand for
CXCR4 corereceptors, creating
effective competition between x4 virus
and the ligand
 RANTES28G mutation increases

12. Primary HIV infection
 Entry of the virus may be through mucosal
surface ,blood ,mother to child during
pregnancy, delivery or by breast milk
 From the mucosal surface carried by dentritic
cells to regional lymphnodes
 the envelope glycoproteins gp41 and gp120
of HIV contain mannose-rich glycans that
bind to mannose-binding proteins (receptors;
also called lectin receptors) on dendritic cells

13. Acute Viraemia
 Virus that enters by blood or blood
products is likely cleared by the spleen
and lymphoid organs ,where replication
resulting to a viraemia occurs
 Abrupt high levels of virus in plasma,
high levels of p24 antigen
 Patient experiences acute
mononucleosis like symptoms as above

14. Primary HIV infection
 Specific immune response occurs with
seroconversion , CD8 cells are
detectable and are responsible for
containment of the virus
 CD4 return to near normal signalling the
end of acute phase
 Viraemia declines, the virus continues
to replicate in CD4 and macrophages

15. Primary HIV
 The viral load at the end of acute phase
is a predictor of progression
 In one study only 8% of pple with a viral
load of 4350 mRNA copies prog to AIDS
in 5 years while in another 62 % with a
viral load of 36270 copies prog to AIDs
in the same period

16. Chronic Phase
 Extensive viral and CD4 turnover occurs
 CD8 cells are continually activated
 After a variable period of time CD4 and
T cells decline
 Hosts defense begins to wane, infected
CD4 cells increase and so is the viral
burden per CD4 cells

17. Chronic Phase
 HIV spill over to the plasma increases
 HIV replication is continues. The virus
evades the immune mechanism by
varying its antigenicity,down regulating
MHC 1 on infected cells so that CD8
cells cannot recognize them

18. Clinical features of HIV
 If untreated critical illness occurs
 Ranges form acute to severe infection
 Early infection and mid infection as
discussed earlier

19. Terminal HIV
 Typical adult patient presents with
- Fever
- Generalised lyphadenopathy
- Diarhea
- Opportunistic infections,neurologic dx and
secondary neoplasia

20. Terminal HIV
• 15 to 30 % dev PJP the risk is high with CD4
< 200
• Candidiasis,CMV,atypical and atypical
Mycobacteria
• Cryptococcus N,Herpes Simplex,Papovavirus
and Histocapsulatum

21. Terminal HIV
 Invasive candiasis common in
neutropenia and in indwelling catheters
 CMV of the retina CD4 of < 50/ul and
GIT as oesophagitis ,colitis and
ulceration
 Out breaks and reactivation of TB is
common, may present with
disseminated M. Avium Intracellulare

22. Terminal HIV
 Cryptococcus occurs in 10% cases
 Diarrhea may result from infections with
salmonella,Shigella,M. Avium
Intracellulare,Isospora or Cryptosporidium
belli
 Tumours KS,Non Hogkins Lyphoma,cervical
ca.,
 25 to 40 % dev malignancy which are caused
by oncogenic viruses due to increased
susceptibility

23. Virological, immunological, and clinical
events in HIV infection

24. WHO disease staging system for HIV
Infection and Disease in Adults and
Adolescents
 Clinical Stage I:
 Asymptomatic
Generalized lymphadenopathy
 Performance scale 1: asymptomatic,
normal activity

25. Clinical Stage II:
 Weight loss <10% of body weight
Minor mucocutaneous manifestations
(seborrheic dermatitis, prurigo, fungal nail
infections, recurrent oral ulcerations, angular
cheilitis)
Herpes zoster within the last five years
Recurrent upper respiratory tract infections
(i.e. bacterial sinusitis)
 And/or performance scale 2: symptomatic,
normal activity

26. Clinical Stage III:
Weight loss >10% of body weight
Unexplained chronic diarrhoea, >1 month
Unexplained prolonged fever (intermittent or constant),
>1 month
Oral candidiasis
Oral hairy leucoplakia
Pulmonary tuberculosis
Severe bacterial infections (i.e. pneumonia,
pyomyositis)
And/or performance scale 3: bedridden <50% of the day
during last month

27. Clinical Stage IV:
HIV wasting syndrome [i]
Pneumocystic carinii pneumonia
Toxoplasmosis of the brain
Cryptosporidiosis with diarrhoea >1 month
Cryptococcosis, extrapulmonary
Cytomegalovirus disease of an organ other than
liver, spleen or lymph node (e.g. retinitis)
Herpes simplex virus infection, mucocutaneous
(>1 month) or visceral
Progressive multifocal leucoencephalopathy

28. Clinical Stage IV:
Any disseminated endemic mycosis
Candidiasis of esophagus, trachea, bronchi
Atypical mycobacteriosis, disseminated or
pulmonory
Non-typhoid Salmonella septicemia
Extrapulmonary tuberculosis
Lymphoma

29. Clinical Stage IV:
Kaposi's sarcoma
HIV encephalopathy [ii]
And/or performance scale 4: bedridden
>50% of the day during last month

30. Footnotes:
i. HIV wasting syndrome: weight loss of
>10% of body weight, + either
unexplained chronic diarrohea (>1
month) or chronic weakness and
unexplained prolonged fever (>1
month).

31. Footnotes:
i. HIV encephalopathy: clinical findings
of disabling cognitive and/or motor
dysfunction interfering with activities of
daily living, progressing over weeks to
months, in the absence of a
concurrent illness or condition, other
than HIV infection, which could
explain the finding