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HIV Diagnosis and Pathogenesis

Scott M. Hammer, M.D.

HIV-1 Virion

Life Cycle of HIV

VIRUS BINDING

AND ENTRY

REVERSEIP I I I

HIV-1

virion

Cell

membrane

Virus

envelope

CD4receptor

Co-

HIV-1

virion

RELEASE

OF PROGENY

VIRUS

BUDDING FROM

HOST CELL

MEMBRANE

I I I I

TRANSLATION

TRANSCRIPTION

PROCESSING

OF PROTEINS

PACKAGING OF

PROTEINS AND GENOME

receptor

HIV Life

Cycle

HIV Entry

HIV Entry

gp120

Anchorage

Co-receptorinteraction

HIV

HIV

gp41

Fusion

Complete

CD4

Attachment

HR1-HR2

interaction

CXCR4

CCR5

CD4

Cell

HIV

gp41

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HIV Integration

Primary HIV Infection:

Pathogenetic Steps

Virus dendritic cell interaction

- Infection is typically w ith R5 (M-tropic) strains

- Importance of DC-SIGN

Acti ve repli cation in l ymphoid t issue

High levels of viremia and di ssemination

Downregulation of virus replication by immune

response

Viral set point r eached after approximately 6

months

PHI: Early Seeding of Lymphoid Tissue

Schacker T et al: J Infect Dis 2000;181:354-357

Primary HIV Infection:

Clinical Characteristics

50-90% of infections are symptomatic

Symptoms generally occur 5-30 days afterexposure

S m toms and si ns- Fever, fatigue, myalgias, arthralgias, headache, nausea,

vomiting, diarrhea

- Adenopathy, ph aryn gi tis , rash , weig ht l oss ,mucocutaneous ulcerations, aseptic meningitis, occas.oral/vaginal candidiasis

- Leukopenia, thrombocytop enia, elevated l iver enzymes

Median duration of symptom s: 14 days

The Variable Course of HIV-1 InfectionTypical Progressor Rapid Progressor

ViralReplication

CD4Level

Primary HIVInfection Cl in ical Latency AIDS

A ViralReplication

CD4Level

Primary HIVInfection AIDS

Bmonths years months years

ViralReplication

CD4Level

months years

Primary HIVInfection Clinical Latency

C

Nonprogressor

?

Reprinted with permission from Haynes. In: DeVita et al, eds. AIDS: Etiology, Treatment and Prevention.

4th ed. Lippincott-Raven Publishers; 1997:89-99.

Primary HIV Infection :

Determinants of Outcome

Severity of symptom s

Viral strain

- SI (X4) vs. NSI (R5) viruses

Importance of GI tract associated lympho id tissu e (GALT)

Immune response

- CTL response

- Non-CTL CD8 responses

- Humoral responses?

Viral set point at 6-24 months post-infection

Other host factors

- Chemokine receptor and HLA genotype

Gender and differences in viral diversity?

Ant ivi ral ther apy

- Near vs. long-term benefit?

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Natural History of UntreatedHIV-1 Infection

1000

800

600Earl O ortun is ti c In fec ti ons+

Time in YearsInfection

Cells400

200

0

Late Opportunistic Infections

1 2 3 4 5 6 7 8 9 10 11 12 13 14

HIV Diagnosis

Consider in anyone presenting with symptoms and signs

compatible with an HIV-related syndrome or in an

asymptomatic person with a risk factor for acquisition

Full sexual and behavioral history shoul d be taken in all

patients

- Assum pti ons of ri sk (or l ack ther eof) by cli nic ians are

unreliable

CDC urging that HIV testing be part of routin e medical care

Laboratory Diagnosis of Established

HIV Infection: Antibody Detection

Screening

- Serum ELISA

- Rapid blood or salivary Ab tests

- Western blot

- In some settings, confirmation of one rapid test is done byperforming a second, different rapid test

Written consent for HIV Ab testing mu st be obtained and beaccompanied by pre-and post-test counselling

- Consent process may change to make it si mpler and easierbut proper counselling remains crucial

Laboratory Diagnosis

of Acute HIV-1 Infection

Patients with acute HIV infection may present to a health

care facility before full antibody serocon version- ELISA may be negative

- ELISA may be positive w ith negative or ind eterminate Western

Plasma HIV-1 RNA level should be done if acute HIV

infection is suspected

Follow-up antibody testing shoul d be performed to

document full seroco nversion (positive ELISA and WB)

Established HIV Infection:

Pathogenesis

Acti ve vi ral r epl icat ion present th rou ghout cou rse o f di sease

Major reservoirs of infection exist outsi de of bloodcompartment

- Lymphoreticular tissues

Gastrointestinal tract (GALT)

- Central nervous s stem

- Genital tract

Virus exists as multiple quasispecies

- Mixtures of viruses with differential phenotypic and genotypiccharacteristics may coexist

At least 10 X 109 virions pro duced and destroyed each day

T1/2 of HIV in plasma is

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Determinants of Outcome:

Selected Viral Factors

Escape from immune response

- Under immune selective pressure (cellular andhumoral), mutations in gag , po l and env may arise

Attenuat ion- nef deleted viruses associated with slow or lo ng-term

nonprogression in case reports and small cohorts

Tropism- R5 to X4 virus conversion associated with increased

viral pathogenicity and disease progression

Subtypes- Potential for differential risks of heterosexual spread or

rates of disease progression

HIV Nomenclature

Groups

- M, N, O

- At l east 9

Sub-subtypes

Circulating recombinant forms

- At l east 15

C

A

DD

CRF02_AG, otherrecombinants

F,G,H,J,K, CRF01other recombinants

B

B, BF recombinant

A, B, AB recombinant

CRF01_AE, B

B, C, BC recombinant

Insufficient

data

GLOBAL DISTRIBUTION OF HIV-1

SUBTYPES AND RECOMBINANTSCourtesy F. McCutchan

Host Factors in HIV Infection (I)

Cell-mediated immuni ty

- Cytotoxic T cells Eliminate virus infected cells

Play prominent role in control of viremia, slowing of

disease progression and perhaps prevention of infection

- T-helper response

Vital for preservation of CTL response

Humoral immunity

- Role in prevention of transmissio n and disease

progression unclear

Role of CTLs in Control o f Viremia

Letvin N & Walker B: Nature Med 2003;9:861-866

Host Factors in HIV Infection (II)

Chemokine receptors- CCR5-32 deletion

Homozygosity associated with decreased susceptibility toR5 virus infection

Heterozygosity associated with delayed disease

- CCR2-V64I mutatio n

Heterozygosity associated with delayed diseaseprogression

- CCR5 promoter polymorph isms

59029-G homozygosity associated with slower diseaseprogression

59356-T homozygosity assoc iated with in creased perinataltransmission

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Host Factors in HIV Infection (III)

Other genetic factors

- Class I alleles B35 and C4

Assoc iated wit h acceler ated di sease pro gress ion

- Heterozygosity at all HLA cl ass I loci

Appear t o be pr otect ive

- HLA-B57, HLA-B27, HLA-B4, HLA-B*5701

Assoc iated wit h lon g-term n on-pr ogres sio n

- HLA-B14 and HLA-C8

?Associated w ith long-term nonprogression

Mechanisms of CD4+ Cell Death

in HIV Infection

HIV-infected cells

- Direct cytotoxic effect of HIV

- Lysis by CTLs

- A o tos is

Potentiated by vi ral gp120, Tat, Nef, Vpu

HIV-uninfected cells

- Apopto sis

Release of gp120, Tat, Nef, Vpu by neighb oring, i nfected

cells

- Acti vati on induc ed cel l deat h

The Variable Course of HIV-1 InfectionTypical Progressor Rapid Progressor

V

iralReplication

CD4Level

Primary HIVInfection Clin ica l Latency AIDS

A ViralReplication

CD4Level

Primary HIVInfection AIDS

Bmonths years months years

ViralReplication

CD4Level

months years

Primary HIVInfection Clinical Latency

C

Nonprogressor

?

Reprinted with permission from Haynes. In: DeVita et al, eds. AIDS: Etiology, Treatment and Prevention.

4th ed. Lippincott-Raven Publishers; 1997:89-99.

Phases of Decay Under the

Influence of Potent Antiretroviral Therapy

RNA

(lo

g10)

0

-1

T1/2 = 1 d (productively i nfected CD4s)

T1/2 = 2-4 wks (macrophages,

2-4 16-24

Time (weeks)

ChangeinHI

-2

a en y n e c e 4 s,

release of trapped virions)T1/2 = 6-44 mos (resting,

memory CD4s)

Therapeutic Implications of First and Second

Phase HIV RNA Decli nes

Anti vir al potency can be assessed in f irst 7-14 days

- Should see 1-2 log declines after initiation of therapy in

persons with drug su sceptible virus who are adherent

HIV RNA trajectory in first 1-8 weeks can be

predictive of subsequent response

- Durability of response translates into clin ical benefit

Phases of Decay Under the

Influence of Potent Antiretroviral Therapy

R

NA

(log10)

0

-1

T1/2 = 1 d (productively i nfected CD4s)

T1/2 = 2-4 wks (macrophages,

2-4 16-24

Time (weeks)

ChangeinHI

-2

a en y n e c e 4 s,release of trapped virions)

T1/2 = 6-44 mos (resting,

memory CD4s)

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+Ag

-Ag

Resting

naveCD4+ T

cell

Activat edCD4+ T

cell

-Ag

Resting

Postintegration

Latency

Preintegration

Latency

Model of Post-Integration Latency

Activat ed

CD4+ T

cell

+Ag

memory

CD4+ T

cell

+Ag +Ag

Siliciano R et al

Therapeutic Implications of Third Phase of

HIV RNA Decay: Latent Cell Reservoir

Viral eradication not possibl e with current drugs

Archiv e of repl ication competent virus his tor y is

established

-

Despite the presence of reservoir(s), minimal

degree of viral evolution observed in patients

with plasma HIV RNA levels

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Non-AIDS Conditions

Since 2006, a number of non-AIDS condition s have been

described to be associated w ith uncontro lled HIV-1 viremia,

even in persons w ith relatively well preserved CD4 cellcounts (e.g., >350/mm3)

- Cardiovascular events

- Hepatic disease

- Renal disease

- Malignancies

Direct effect of HIV-1 on or gan systems, associated immun e

activation and/or other mechanisms may be involved

Acti ve area of i nves tig atio n

Redefining HIV-related disease progression and influencin g

decision of wh en to start ART

Prognosis Accord ing to CD4 and RNA:

ART Cohort Collaboration

Egger M et al: Lancet 2002;360:119-129

Progress in HIV Disease

HIV Pathogenesis

Monitoring Therapy