HIV-1 Primarily Targets the Innate Immune System and Only Secondarily Modulates Adaptive Immune Cell Depletion

doi:10.4236/wja.2012.23029

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World Journal of AIDS, 2012, 2, 226-231

http://dx.doi.org/10.4236/wja.2012.23029 Published Online September 2012 (http://www.SciRP.org/journal/wja) 223

HIV-1 Primarily Targets the Innate Immune System and

Only Secondarily Modulates Adaptive Immune Cell

Depletion

Lawrence M. Agius1,2

1Department of Pathology, Mater Dei Hospital, Tal-Qroqq, Malta; 2University of Malta Medical School, Msida, Malta.

Email: [email protected], [email protected]

Received April 21st, 2012; revised May 14th, 2012; accepted May 25th, 2012

ABSTRACT

Persistence of HIV-1 infection allows for permissive microenvironmental conditioning in terms of contextual innate

immune participation. The progression of host cell injury constitutes an additional parametric formulation in self-am-

plifying modulation of the adaptive immune response in a manner that inclusively promotes the emergence of a final

stage of AIDS that is both depletive and permissive for opportunistic infections and various forms of neoplasia. It is

within contextual indices of promotion of depleted T-helper lymphocytes and of augmented viremic loads that manifest-

tations of classic lesions emerge as the AIDS phenomenon. It is further to be realized that an apoptotic response of mul-

tiple cell subtypes including T-lymphocytes includes host-cell participation within formulated settings of further persis-

tence of the retroviral infection. An all-inclusive phenomenon of dendritic cell-lymphocyte synapse formulation corre-

sponds to the establishment of HIV-1 infection that specifically conditions all subsequent stages in depletion of the in-

jured host cells regardless of the dynamics or kinetics of the retroviral replicative infectious process itself.

Keywords: HIV-1; Infection; Aids; Immune; Persistence

1. Introduction

HIV-1 infection is inherently a progressive disorder that

is especially productive of a chronic participation of in-

jury to CD4+ T-lymphocytes within additional contex-

tual conditioning of the AIDS phenomenon. This inher-

ently progressive infection is suggestive in itself of a

profound involvement of the innate immune system in

particular. Interferon lamba 3 activates the innate im-

mune system through the JAK-STAT pathway in macro-

phages. It inhibits HIV-1 replication in these cells and

induces many antiviral cellular factors and interferon

regulatory mediators [1]. Plasmacytoid dendritic cells

serve as an essential link between innate and adaptive

immune systems; the fate of these cells in HIV-1 infec-

tion is unclear [2]. The realization of monocyte/macro-

phage participation in the accumulation of the HIV-1

virions indicates the essential character of an infection

that arises primarily from innate immune defects. Macro-

phages and their monocyte precursors show marked het-

erogeneity and may be either proinflammatory or alter-

natively activated [3].

The ongoing development of infection to multiple he-

matopoietic cell lineages is a highly prominent feature of

injury that is ultimately the criterion for the ensuing in-

fection that is manifested primarily as acquired immune

deficiency. CNS opportunistic infections vary according

to HIV induced defects of innate immunity versus ab-

normal adaptive immunity [4].

The emergence of cellular injury therefore constitutes

the establishment of multi-lineage cellular injury that is

productive of the progressive nature to the AIDS pan-

demic. B lymphocyte abnormalities precede CD4(+) T

cell decline [5].

2. Cascade Events

The closely parallel involvement of systems of cascade

signalling in HIV-1 infected cell lines correlates espe-

cially with the recombinant HIV-1 virion variants that

establish themselves in the circulating blood of persis-

tently infected individuals. The further emergence of

highly characteristic opportunistic infections and also

especially of different forms of neoplasia are further

promotional events in the establishment of progression as

the main pathogenic mechanisms leading to the AIDS

process. Chronic immune activation appears to result

from untimely innate immune responses and is believed

to be implicated in dynamics of emergence of AIDS in

HIV-1 infected individuals [6].

HIV-1 Primarily Targets the Innate Immune System and Only Secondarily Modulates Adaptive Immune Cell Depletion 227

Indications of non-resolution of the HIV-1 infection

arise as perpetuating involvement by a virion that is rela-

tively slowly replicative but that is capable of exquisite

evasion of the immune system. HIV-1 Nef appears im-

portant in HIV-1 transmission by dendritic cells to acti-

vated CD4(+) T cells [7]. Vpu promotes suppression of

innate immunity and counteracts natural killer cells by

interfering with CD1d expression and antigen presenta-

tion; it also suppresses expression of NK-T and B cell

antigen [8].

Recombinant variants of this retrovirus indicate the

enormous capability for adaptability to a changing mi-

croenvironment in terms of the further participation of

injury to multiple cell types. In this regard, the essential

representation of the infectious process is closely allied

to a formulated recombinatio n of multiple sero-strains as

further evidenced by subtypes of the HIV-1 virion M, O

and N, and by the subtypes of the M variant itself.

3. HIV-1 Progression

Indications of realization of HIV-1 progression appear to

arise primarily as a consequence of chemokine and cyto-

kine pathobiology as relative especially to coreceptors to

the CD4+ receptor. IL-7 effectively protects the CD4(+)

T cell pool during acute SIV infection in macaques [9].

The attributes of complicatin g neoplastic lesions in these

patients are closely formulated consequences of the pro-

longed persistence of a dual coinfection by both HIV-1

and accompanying oncogenic viruses such as human

herpes virus-8, Ebstein-Barr virus and human papilloma

virus subtypes.

In such manner, proportional accumulation of HIV-1

virions within persistently infected host cells correlates

with the emergence of depletion of the CD4+ T lympho-

cytes and of the increasing circulating viremic load.

Macrophages are essentially implicated in HIV-1 in-

fection, viral rebound and clinical emergence of AIDS

[10]. Glutathione-enhanced natural killer cells tend to

suppress mycobacterial tuberculosis infection within

human monocytes [11].

Establishment of the HIV-1 infection arises as a main

consequence of an activation phenomenon that affects

both T and B lymphocytes. In such manner, the cones-

quential attributes of recombinant subtypes of coinfect-

ing HIV-1 virions indicate a prominent derived character

for persistence towards the development of a profound

immune deficiency.

High levels of viremia in the establishment of the infec-

tious process reflect an adherence of patterned formula-

tion within pathways and cascades that include a promi-

nent paracrine microenvironmental effect. The innate

immune response appears a critical factor in initial HIV

transmission and dissemination, implicating type I inter-

feron, defensins and whey acidic proteins [16]. Enhanced

IL-2 production and improved proliferation of CD4 T

helper cells are restricted to viremic individuals. When

regulatory T cells are depleted from circulating mono-

cytes in viremic patients, IL-10 production decreases and

proinflammatory cytokines increase [17]. In this regard

the participation of multiple c ellu lar lineag es co llaborates

The latter phenomenon is itself a source for sequential

transformation of cells towards malignant neoplastic

emergence. Vpu (viral protein U) may have evolved as a

promoter of human-to-human HIV-1 transmission due to

an interplay between viral factors versus host restriction

factors [12].

4. Disease Setting

The whole setting of attributes of HIV-1 infection is con-

clusive parameter for the induction of further cellular

injury that primarily includes depletion of lymphocyte

subsets without in fact direct overwhelming infection of

such lymphocytes. In such manner, profound immune

cell depletion is a complex evolution involving by-

stander effect and also the induction of apoptosis of mul-

tiple cell-subtypes. Premature immunosenescence of the

innate immune system may be mediated by chronic en-

dotoxemia, residual viremia, telomere attrition and al-

tered cellular signallin g [13].

Inflammation is an exquisite setting for the production

of cellular injury in AIDS infections in a further contex-

tual setting of persistent HIV-1 infection. Leukotrienes

influence microglial infection and may partly control

viral load in the central nervous system [14]. It is with

regard to a multiplicity of step s in the production of new

retroviral virions that a whole panorama of adaptive

change involves an inflammatory response to the viral

infection and to the persistent process of immune defi-

ciency state leading generally to the AIDS process.

Activation of lymphocytes characterizes the early

stages of HIV-1 infection with the profound incorpora-

tion of replicative viral activity especially within mono-

cytes/macrophages. Type I interferon response by the

innate immune system is produced by plasmacytoid den-

dritic cells and appears to control HIV-1 productive in-

fection and disease progression [15].

Formulated patterns include the emergence of system-

atic processes of integration of the cDNA of the HIV-1

genome in manners that implicate insertional mutagene-

sis. The further confounding chemokine and cytokine

accompaniments by such factors as activation of the viral

reverse transcriptase indicate an overall close homology

of virion capability towards host-cell components as fur-

ther evidenced by the persistent articulation of cellular

injury to CD4+ T helper lymphocytes.

5. Viremia

HIV-1 Primarily Targets the Innate Immune System and Only Secondarily Modulates Adaptive Immune Cell Depletion

228

with the involvement of multiple cell-signalin g pathways

that promote adaptive potentiality towards the host cell

that is infected. Homology of genomic components of the

virion correlates with the adoption of multiple parameters

that belie a single main pathogenic mechanism in reach-

ing establishing persisten ce of the HIV-1 infection.

6. Activation

It is in terms of adherence of host-cell response as activ-

tion mechanisms that promote a realization of cellular

injury that there is included widespread apoptosis of T

helper lymphocytes.

Correlates of a promotional nature that are mainly

characterized by a marked activation of lymphocyte sub-

sets include the formulation for further persistence of cell

injury within contextual reproduction of multiple promi-

nent lineage participations. Plasmacytoid dendritic cells

possibly enable HIV-1 elite controllers to control HIV-1

viremia [18]. Activated nervous system mononuclear

phagocytes and astrocytes expressing HIV-1 gene prod-

ucts in specific patterns may promote neurodegeneration

[19]. It is in a microenvironmentally conditioned in-

flammatory response that parameters of spread of the

HIV-1 virus include the evolution of viral resistance to

various drug treatment protocols that is commonly seen

in patients treated with anti-retroviral therapy.

Included participation of multiple cell-type infection in

HIV-1 phases of evolution allow for the development of

specific regulatory disorders that incorporate the persis-

tent infection. Intrinsic antiviral immunity tends to re-

strict infection by blocking viral replication directly in an

immediate manner [20]. Replicative activity of the retro-

virus is accompanied by a very high mutability that

self-promotes the ensuing infection as productive of the

AIDS stage of infection.

7. Aids Phase

In terms of such ongoing participation of cellular injury

in the creation of a conducive setting for persistence of

the HIV-1 infection, it is a dual involvement of inflam-

matory reactivity with the emergence of subsequent se-

vere immune deficiency that permits evolution of pat-

terns of modulated participation of such cellular injury to

lymphocyte depletion and AIDS phase establishment.

Toll-like receptors as innate immune components induce

activation of NF-kappaB that in turn promotes HIV-1

replication [21]. Humanized mice are optimal for study-

ing HIV-1 immunopathogenesis and for the development

of novel immune-based th erapies [22].

Indicative inclusion of mutability would allow for the

acquisition of a capability for pronounced depletion of

immune cells as these relate particularly to impaired ex-

pression of human histocompatibility antigens. The den-

dritic cells in particular appear a primal form of pattern ed

involvement in patients infected with HIV-1. It is in

terms of augmented activation of immune cells on the

one hand and o f impaired resolution of the cellular injury

that inflammatory microenvironmental paracrine effect

further promotes the emergence of injury to lymph nodes

and gastrointestinal associated lymphoid tissue. Fibrosis

accompanies a severely progressive lymphocytic deple-

tion in modes of further involvement of the innate im-

mune system in particular. Dendritic cells are partici-

pants in the production of spread of the HIV-1 infection

as evidenced by monocytes/macrophages that accumulate

highly replicative sites for the retrovirus.

Polymorphisms of innate immune genes affecting

Toll-like receptors and defensins modulate progression

of HIV-1 infection in children [23]. Inclusion dynamics

of the virion particles promote establishment of inte-

grated viral genomes within host-cell genomes as indi-

cated by the elaborate phases of entry and attachment to

the cell membrane, the reverse transcription of the viral

RNA genome and the formulation of transport of viral

components from the nucleus to the cytoplasm and plas-

malemma. CD4 binding site directed inhibitors (mono-

clonal antibodies) act preferentially by blocking free vi-

rus transmission while still allowing HIV-1 to spread

through cell-cell contacts [24].

The failure to recognize a single essential pathogenic

step in HIV-1 infection is symptomatic of a variety of

inducing environments that promote the production of

further attributes of the overall persistence of the viral

replication and release. The neutralizing antibody con-

stant domain functionally links innate and adaptive im-

mune systems to harness innate immune response [25].

In primary HIV-1 infection there develops dysfunction of

dendritic cells and this is independ ent of interaction with

gp120 [26].

8. Micro-Environment

Inclusive formulations of multiple component pathways

are irreducible parameters in the development of such

micro-environmental conditioning.

In such terms, inclusive forces such as pressure-in-

duced mutability of the HIV-1 genome, including such

factors as anti-retroviral drug therapy, affect the pathobi-

ologic attributes of the AIDS syndrome phase. Within a

range phenomenon of inclusive parameters, the HIV-1

infection arises largely as an integral component of the

micro-environmental milieu of inflammation and of

evolving immune deficiency. Autophagy is increasingly

being implicated in pattern recognition paradigms af-

fecting innate immunity [2 7].

TRIM5 as a restriction factor may indicate how the

innate immune system detects distinct molecular features

of HIV-1 [28].

HIV-1 Primarily Targets the Innate Immune System and Only Secondarily Modulates Adaptive Immune Cell Depletion 229

Promotional attributes of cohesive participating roles

in such micro-environmental conditioning indicates that

HIV-1 is a privileged infectious agent that creates and

modulates multiple facets of inclusive formulation that

are directed primarily in the creation of recombinant

forms of the virion in the individual patient with AIDS. It

is further to be noted that the innate immune system in-

volvement accounts for the establishment of multiple

facets of involvement as coreceptivity as promoted by

disordered chemokine and cytokine biology. Host inva-

sion and viral replication appear orchestrated by Nef ac-

tions in macrophages including receptor expression, in-

tracellular signalling and production of mediators of in-

flamma tion [29].

Of particular relevance is the dendritic cell-lympho-

cyte/macrophage synapse in infectious modes of modu-

lated effect leading to a process of accumulation relevant

towards the ongoing persistence of the infection by

HIV-1 virus. Virological synapses between infected den-

dritic/T lymphocytes and uninfected T cells may very

well prove the do minant mode of HIV-1 spread [30]. Th e

attributes of activation of lymphocytes are clearly also a

modulation step in the evolution of the retroviral infec-

tion as an established persistence of further induction in

microenvironmental conditioning. The emergence of

multiple forms of neoplasia in the AIDS patient is sug-

gestive also of endothelial cell participation, particularly

within a setting of augmenting viremic levels that circu-

late in the peripheral blood.

9. Redistribution

An inclusively overall parameteric redistribution of the

HIV-1 virions accounts for the promotional persistence

as evidenced by a clinical setting of multiple forms of

opportunistic infection and of neoplastic lesions includ-

ing Kaposi sarcoma, non-Hodgkin lymphoma, and cer-

vical carcinoma. In such terms, implication of further

evolving pathogenesis allows a permissive environment

that conditions also the profound immune deficiency. In

effective terms, the whole integrative phenomenon of per-

sistent HIV-1 infection is a parent process of subsequent

derivative pathways of essential amplifying proportions.

Inflammasome genes are implicated in susceptibility

to HIV-1 infection [31]. The processes of derivative pa-

rameters are all-inclusive formulations that essentially

modulate the innate immune pathways as primary con-

stitutive targets of HIV-1 rather than as a primary infec-

tion of T lymphocytes per se. It is with reference to mul-

tiple inducible pathways of reproduction that macro-

phages, natural killer cells and dendritic cells promote a

setting of modulated permissiveness that contributes di-

rectly to the establishment of the persistent nature of the

HIV-1 infection. Strong antibody mediated activation of

Natural Killer cells to HIV-1 Env occurs in persistent

HIV-1 infection [32].

Apoptosis may be viewed as an essential reflection of

such amplifying microenvironmental conditioning with

regard to secondary acquisition of the T helper lympho-

cyte depletion.

Activation of both T and B lymphocytes appears a

correlative phenomenon in itself that demarcates potenti-

ality for persistence of the retroviral infection. A promo-

tional accumulative viral load empowers the emergence

of persistent viral infection, regardless of the degree of

viral particle replication within specific cellular or im-

mune cellular subsets. HIV-1 is able to productively in-

fect nondividing cells as well as dividing cells at inter-

phase by actively delivering its DNA into the nucleus by

means of ho st nuclear impor t machine ry [33].

Replicative activity of host cells correlates with viral

replication formulas and promotes the microenviron-

mental conditioning that harbors further potential non-

resolution of cell injury of virally infected host cells.

Redistribution of lymphocytes and also of other cell-

types such as dendritic cells promotes a systemically

promotional effect to HIV-1 infection as also noted with

regard to the AIDS phase of infection.

10. Concluding Remarks

Parameters of induction and non-resolution of HIV-1

infection indicate an exquisite acquisition of a self-am-

plifying range of potentialities th at specifically indicate a

primary all-embracing involvement of the innate immune

system; this responds by implicating in secondary fash-

ion a pathobiologic activation of the adaptive immune

response.

Further evolution of the retroviral infection imposes

pressure effects on multiple cell subtypes in a manner

that implicates cytokine and chemokine modulation

within a microenvironmental inflammatory milieu. The

apoptosis of host cells is sharply distin ct from a dynamo-

ics that solely targets such cells as replicative reservoirs

of the HIV-1; this phenomenon is suggestive of a modu-

lation that is specifically both an activating and dep letive

inclusive formulation of viremic and host-cell co-infec-

tivities.

A systemic redistribution of host cell injury evolves

within a contextual representation of multiple cell sub-

types ranging from macrophages, dendritic cells, natural

killer cells to endothelial cells in inducing persistence of

the infection as the one paramount dynamics of HIV-1

involvement of the individual patient progressing to

AIDS as a distinct disease phase.

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