HIV AND TB VACCINES: HIV AND TB VACCINES: OBSTACLES MET AND OBSTACLES MET AND PROGRESSES MADEPROGRESSES MADE
HIV: Virion (Virus Particle)
gp120
gp41
viral envelope glycoproteins
lipid membrane of
envelope (host derived)
matrix (p17)viral core
(p24)
reverse transcriptase
viral RNA (ss) (2 copies)
HIV Virion StructureHIV Virion Structure
Course of HIV infection
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 12
Weeks Years
Primary Infection Seeding of lymphoid organs
Dissemination
0
250
500
750
1000
CD
4 co
unt (
cells
/µl)
Clinical Latency
Virus R
NA
(copies/ml)
AIDS (Opportunistic
Infections)
Modified from Sabin et al. JAIDS 23:172, 2000.
~0.1 log per year rise in HIV load
10
10
10
10
10
6
5
4
3
2
Course of HIV InfectionCourse of HIV Infection
Genes in HIV Genes in HIV GAGGAG
It makes various proteins necessary to protect the virus. It makes various proteins necessary to protect the virus. In HIV, it has three parts: MA (matrix), CA (capsid), and In HIV, it has three parts: MA (matrix), CA (capsid), and NC (nucleocapsid)NC (nucleocapsid)
POLPOLIt makes enzymes necessary for virus replication. In HIV, It makes enzymes necessary for virus replication. In HIV, it also has three parts: PR (protease), IN (endonuclease), it also has three parts: PR (protease), IN (endonuclease), and RT (reverse transcriptase)and RT (reverse transcriptase)
ENVENVThe envelope gene is also found in all retroviruses. It The envelope gene is also found in all retroviruses. It makes proteins for the envelope to the virus. In HIV, it makes proteins for the envelope to the virus. In HIV, it has two parts. SU (surface envelope, gp120) and TM has two parts. SU (surface envelope, gp120) and TM (transmembrane envelope, gp41)(transmembrane envelope, gp41)
Genes in HIV Genes in HIV
tattatThe transactivator gene influences the function of genes The transactivator gene influences the function of genes some distance away. It controls transactivation of all HIV some distance away. It controls transactivation of all HIV proteins.proteins.
revrevThe differential regulator of expression of virus protein The differential regulator of expression of virus protein genes. genes.
vifvifThe virus infectivity factor gene is required for infectivity The virus infectivity factor gene is required for infectivity as cell-free virus. as cell-free virus.
nefnefThe negative regulator factor retards HIV replication.The negative regulator factor retards HIV replication.
Genes in HIV Genes in HIV
vprvprThe virus protein R gene has an undetermined functionThe virus protein R gene has an undetermined function
vpuvpuThe virus protein U gene is required for efficient viral The virus protein U gene is required for efficient viral replication and release. It is found only in HIV-1replication and release. It is found only in HIV-1
vpxvpxThe virus protein X gene has an undetermined The virus protein X gene has an undetermined function. It is found only in HIV-2 and SIV function. It is found only in HIV-2 and SIV
Antigen Presenting Cells*“First-line Defense”*Involved in capturing antigen*Display ‘foreign’ antigens to activate T Cells
T Cells*Involved in the ‘killing’ ofvirus-infected cells*Adaptive Immunity
B Cells*Involved in making antibodies*Adaptive Immunity
Requisites for a Requisites for a successful HIV vaccine:successful HIV vaccine:
AntibodiesAntibodies
Bind virus; neutralize or stop virus from Bind virus; neutralize or stop virus from infecting cells; eliminate virusinfecting cells; eliminate virus
Cytotoxic T lymphocytesCytotoxic T lymphocytes
Recognize cells infected with virus and Recognize cells infected with virus and kill those cellskill those cells
High mutability of virusHigh mutability of virus
No protective correlate definedNo protective correlate defined
Multiple clades all over the globeMultiple clades all over the globe
HIV VACCINES – WHY SUCCESS IS HARD?
Strains / Clades
C
CC
E
BB
B A,D E
CC
C
B
BB
2A-HO, N
B
Clades differ by around 20% of RNA and Protein sequence
What are the steps in What are the steps in Vaccine development?Vaccine development?
Phase I: 10-30 volunteers, 8-12 months
Phase II: 50-500 volunteers,18-24 months
Phase III: Thousands of volunteers, 3 or more years
What types of HIV vaccines are What types of HIV vaccines are being tested?being tested?
Peptide epitopes (protein fragments)
Live attenuated HIV
Whole, killed HIV
Naked DNA
Types of HIV vaccinesTypes of HIV vaccines
Recombinant Viral Proteins
Live bacterial vectors
Live Viral Vectors
Pseudovirions
HIV vaccines in clinical trials HIV vaccines in clinical trials for efficacy and for efficacy and immunogenicityimmunogenicity
Conclusions
Increasing understanding of how the immune response attempts to control HIV infection and how HIV evades this
Attempts to make a vaccine have been so far unsuccessful traditional approaches
Promising new approaches to prophylactic vaccines
Therapeutic vaccines may improve therapy
However, vaccines still several years away
TB statistics : 2006TB statistics : 2006
Globally, 9.2 million new cases Globally, 9.2 million new cases
1.7 million deaths from TB 1.7 million deaths from TB
0.7 million cases and 0.2 million deaths 0.7 million cases and 0.2 million deaths were in HIV-positive people were in HIV-positive people
BCG VACCINEBCG VACCINE
Deletion mutant of Deletion mutant of M.bovisM.bovis
Protects against childhood meningeal TB Protects against childhood meningeal TB
and disseminated TBand disseminated TB
Protection low in developing countriesProtection low in developing countries
Replacement BCG Replacement BCG vaccinesvaccines
rBCG30rBCG30
Hyperexpression of Ag85BHyperexpression of Ag85B
rBCG: rBCG: UreC:hly+UreC:hly+
Urease gene deleted and listeriolysin gene Urease gene deleted and listeriolysin gene incorporated BCG incorporated BCG
Boosting BCG vaccinesBoosting BCG vaccines
Ag85B-ESAT-6/TB10.4 fusion protein constructAg85B-ESAT-6/TB10.4 fusion protein construct
Mtb72f Mtb72f
Fusion protein of Mtb32 and Mtb39 proteinsFusion protein of Mtb32 and Mtb39 proteins
MV85AMV85A
Modified Vaccinia construct with Antigen 85AModified Vaccinia construct with Antigen 85A